PROCESSES AND INTERMEDIATES FOR PREPARING alpha,omega-DICARBOXYLIC ACID-TERMINATED DIALKANE ETHERS

ABSTRACT

The present disclosure provides a process for the preparation of compounds of formula (III), 
     
       
         
         
             
             
         
       
     
     compounds of formula (V), 
     
       
         
         
             
             
         
       
     
     and corresponding salts of formula (IV). 
     
       
         
         
             
             
         
       
     
     The compounds made by the methods and processes of the invention are particularly useful for administration in humans and animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 14/942,765,filed Nov. 16, 2015, which claims the benefit of U.S. ProvisionalApplication No. 62/079,894, filed Nov. 14, 2014, each of which is herebyincorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

α,ω-Dicarboxylic acid-terminated dialkane ethers have activity inlowering several plasma lipids, including Lp(a), triglycerides,VLDL-cholesterol, and LDL-cholesterol, both in animals and in humans.See U.S. Pub. No. 2010/0256209. The compounds also are known to increaseinsulin sensitivity. See U.S. Pub. No. 2010/0256209. In particular,6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid) (also known as6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid), whose USANname is gemcabene, and its calcium salt (gemcabene calcium) have beenintensively studied in multiple clinical trials as a lipid loweringagent for the treatment of patients with low high-density lipoprotein(HDL) and high low density lipoprotein (LDL). See Bays, H. E., et al.,Amer. J. Cardiology, 2003, 92, 538-543. Gemcabene has been clinicallytested as an anti-hypertensive and anti-diabetic agent in addition tothe lipid lowering activity.

A synthetic method for the preparation of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) and other α,ω-dicarboxylicacid-terminated dialkane ethers is described by Bisgaier, C. L. et al.in U.S. Pat. No. 5,648,387, which is incorporated herein by reference inits entirety. In addition, preparation and characterization of alcoholand water solvates of 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium(gemcabene calcium), for the treatment of dyslipidemia, vasculardisease, and diabetes are disclosed in U.S. Pat. No. 6,861,555, which isincorporated herein by reference in its entirety. Zhang, Y et al. alsoreport a small scale synthesis of C-14- and tritiated-gemcabenecongeners in J Label Compd Radiopharm 2007, 50, 602-604.

The previously disclosed syntheses raise a number of safety andenvironmental concerns when replicated on a scale larger than 1 kg.Thus, a need remains for safe and environmentally friendly processes forpreparing α,ω-dicarboxylic acid-terminated dialkane ethers on a largescale.

SUMMARY OF THE INVENTION

These and other needs are met by the current disclosure, which providesgeneral and industrially-scalable methods for the preparation ofα,ω-dicarboxylic acid-terminated dialkane ethers and salts thereof.

The present disclosure provides a process for the preparation ofcompounds of formula (III),

compounds of formula (V),

and corresponding salts of formula (IV):

wherein M¹ is an alkaline earth metal or alkali metal.

The compounds made by the methods and processes of the invention areparticularly useful for administration in humans and animals.

One aspect of the invention is a process for preparing a compound offormula (III):

wherein:

R¹ is alkyl;

R² and R³ are each independently alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl; and

n and m are each independently 0-4;

comprising:

-   -   (a) reacting a solution comprising a substituted acetic acid        ester of formula (I):

with a deprotonating reagent to produce an intermediate of formula (Ia):

wherein M² is Li or Zn; and

-   -   (b) reacting the intermediate of formula (Ia) with a solution        comprising a α,ω-halo-terminated dialkane ether of formula (II):

wherein X is a halogen;

to produce a compound of formula (III).

A further aspect of the invention is the process for preparing acompound of formula (III):

wherein:

R¹ is alkyl;

R² and R³ are each independently R² and R³ are each independently alkyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, or heteroarylalkyl; and

n and m are each independently 0-4;

comprising:

-   -   (a) reacting a solution comprising an α-bromo-acetic acid ester        of formula (IX):

with a metal, until the metal is essentially dissolved;

-   -   (b) reacting the solution of step (a) with a solution comprising        a α,ω-halo-terminated dialkane ether of formula (II):

wherein X is halo;

to produce a compound of formula (III).

In other aspects, the compound of formula (III) is hydrolyzed to producea compound of formula (V).

In some aspects, the compound of formula (V) is6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, the saltof formula (IV) is the calcium salt of6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

In some aspects, the compound of formula (III) is a compound of formula(48).

In some aspects, the compound of formula (V) is a compound of formula(49).

In some aspects, the salts of formula (IV) are salts of formula (50).

A further aspect discloses a process for preparing a compound of formula(48):

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a first solution of a compound of formula (46):

-   -   -   with a halogen source to produce an intermediate of formula            (47):

wherein X²⁴ is F, Cl, or I and where R²¹ is alkyl;

-   -   (b) reacting a second solution of the compound of formula (46)        with the intermediate of formula (47) in the presence of base to        form a compound of formula (48).

In some embodiments, step (a) is in the presence of triphenylphosphine.

In one embodiment, the first compound of formula (46) and the secondcompound of formula (46) have identical substituents R²¹, R²² and R²³,and m is the same. In another embodiment, they are different.

In other aspects, the compound of formula (48) is hydrolyzed to producea compound of formula (49).

In some aspects, the compound of formula (49) is6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid). In other aspects, thecompound of formula (50) is the calcium salt of6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

In a further aspect, a compound of formula (48):

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;

comprising:

-   -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45):

-   -   (e) reacting the solution of a compound of formula (45) with        potassium tert-butoxide to produce an intermediate of formula        46):

-   -   (f) reacting the solution of a compound of formula (46) with a        halogen source in the presence of triphenylphosphine to produce        an intermediate of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting the solution of a compound of formula (46) with the        intermediate of formula (47) in the presence of base to form a        compound of formula (48):

-   -   (h) reacting the solution of a compound of formula (48) with        dilute acid to form (49).

A further aspect is a process for preparing a compound of formula (45):

wherein:

-   -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45).

DETAILED DESCRIPTION OF THE INVENTION Abbreviations and Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning ° C. Degrees Celsius DMF Dimethylformamide DMSODimethyl Sulfoxide Et Ethyl Eq Equivalent HDL High-Density LipoproteinHr Hour LDA Lithium Diisopropylamide LDL Low-Density Lipoprotein Lp(a)Lipoprotein (a) M Molar Min Minute RT Room Temperature VLDL VeryLow-Density Lipoprotein

The symbol “-” means a single bond, and “=” means a double bond.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to 6 carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl (including all isomeric forms), or pentyl (including allisomeric forms), and the like.

“Alkylamino” means an —NHR group where R is alkyl, as defined herein.

“Alkylsilyl” means an alkyl group substituted with at least one silylgroup, as defined herein.

“Amino” means —NH₂.

“Aminoalkyl” means an alkyl group substituted with at least one,specifically one, two or three, amino groups.

“Aryl” means a monovalent six- to fourteen-membered, mono- orbi-carbocyclic ring, wherein the monocyclic ring is aromatic and atleast one of the rings in the bicyclic ring is aromatic. Unless statedotherwise, the valency of the group may be located on any atom of anyring within the radical, valency rules permitting. Representativeexamples include phenyl, naphthyl, and indanyl, and the like.

“Arylalkyl” means an alkyl radical, as defined herein, substituted withone or two aryl groups, as defined herein, e.g., benzyl and phenethyl,and the like.

“Cycloalkyl” means a monocyclic or fused bicyclic, saturated orpartially unsaturated (but not aromatic), monovalent hydrocarbon radicalof three to ten carbon ring atoms. Fused bicyclic hydrocarbon radicalincludes bridged ring systems. Unless stated otherwise, the valency ofthe group may be located on any atom of any ring within the radical,valency rules permitting. One or two ring carbon atoms may be replacedby a —C(O)—, —C(S)—, or —C(═NH)— group. More specifically, the termcycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexyl, or cyclohex-3-enyl, and the like.

“Cycloalkylalkyl” means an alkyl group substituted with at least one,specifically one or two, cycloalkyl group(s) as defined herein.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedherein, or an N-oxide derivative, or a protected derivative thereof,e.g., dimethylamino, diethylamino, N,N-methylpropylamino orN,N-methylethylamino, and the like.

“Halo” or “halogen” refers to fluorine, chlorine, bromine, or iodine.

“Haloalkyl” mean an alkyl group substituted with one or more halogens,specifically one to five halo atoms, e.g., trifluoromethyl,2-chloroethyl, and 2,2-difluoroethyl, and the like.

“Heteroaryl” means a monocyclic, fused bicyclic, or fused tricyclic,monovalent radical of 5 to 14 ring atoms containing one or more,specifically one, two, three, or four ring heteroatoms independentlyselected from —O—, —S(O)N— (n is 0, 1, or 2), —N—, —N(R^(x))⁻, and theremaining ring atoms being carbon, wherein the ring comprising amonocyclic radical is aromatic and wherein at least one of the fusedrings comprising a bicyclic or tricyclic radical is aromatic. One or tworing carbon atoms of any nonaromatic rings comprising a bicyclic ortricyclic radical may be replaced by a —C(O)—, —C(S)—, or —C(═NH)—group. R^(x) is hydrogen, alkyl, hydroxy, alkoxy, acyl, oralkylsulfonyl. Fused bicyclic radical includes bridged ring systems.Unless stated otherwise, the valency may be located on any atom of anyring of the heteroaryl group, valency rules permitting. When the pointof valency is located on the nitrogen, R^(x) is absent. Morespecifically, the term heteroaryl includes, but is not limited to,1,2,4-triazolyl, 1,3,5-triazolyl, phthalimidyl, pyridinyl, pyrrolyl,imidazolyl, thienyl, furanyl, indolyl, 2,3-dihydro-1H-indolyl(including, for example, 2,3-dihydro-1H-indol-2-yl or2,3-dihydro-1H-indol-5-yl, and the like), isoindolyl, indolinyl,isoindolinyl, benzimidazolyl, benzodioxol-4-yl, benzofuranyl,cinnolinyl, indolizinyl, naphthyridiN-3-yl, phthalaziN-3-yl,phthalaziN-4-yl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl,tetrazoyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl,isooxazolyl, oxadiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl,tetrahydroisoquinolinyl (including, for example,tetrahydroisoquinolin-4-yl or tetrahydroisoquinolin-6-yl, and the like),pyrrolo[3,2-c]pyridinyl (including, for example,pyrrolo[3,2-c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl, and the like),benzopyranyl, thiazolyl, isothiazolyl, thiadiazolyl, benzothiazolyl,benzothienyl, and the derivatives thereof, or N-oxide or a protectedderivative thereof.

“Heteroarylalkyl” means an alkyl group, as defined herein, substitutedwith at least one, specifically one or two heteroaryl group(s), asdefined herein.

“Heterocycloalkyl” means a saturated or partially unsaturated (but notaromatic) monovalent monocyclic group of 3 to 8 ring atoms or asaturated or partially unsaturated (but not aromatic) monovalent fusedbicyclic group of 5 to 12 ring atoms in which one or more, specificallyone, two, three, or four ring heteroatoms independently selected from O,S(O)_(n) (n is 0, 1, or 2), N, N(R_(y)) (where R_(y) is hydrogen, alkyl,hydroxy, alkoxy, acyl, or alkylsulfonyl), the remaining ring atoms beingcarbon. One or two ring carbon atoms may be replaced by a —C(O)—,—C(S)—, or —C(═NH)— group. Fused bicyclic radical includes bridged ringsystems. Unless otherwise stated, the valency of the group may belocated on any atom of any ring within the radical, valency rulespermitting. When the point of valency is located on a nitrogen atom,R^(y) is absent. More specifically the term heterocycloalkyl includes,but is not limited to, azetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl,2,5-dihydro-1H-pyrrolyl, piperidinyl, 4-piperidonyl, morpholinyl,piperazinyl, 2-oxopiperazinyl, tetrahydropyranyl, 2-oxopiperidinyl,thiomorpholinyl, thiamorpholinyl, perhydroazepinyl, pyrazolidinyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,oxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl,quinuclidinyl, isothiazolidinyl, octahydroindolyl, octahydroisoindolyl,decahydroisoquinolyl, tetrahydrofuryl, and tetrahydropyranyl, and thederivatives thereof and N-oxide or a protected derivative thereof.

“Heterocycloalkylalkyl” means an alkyl radical, as defined herein,substituted with one or two heterocycloalkyl groups, as defined herein,e.g., morpholinylmethyl, N-pyrrolidinylethyl, and3-(N-azetidinyl)propyl, and the like.

As used herein, the term “silyl” includes tri-lower alkylsilyl groupssuch as a trimethylsilyl group, a triethylsilyl group, anisopropyldimethylsilyl group, a t-butyldimethylsilyl group, amethyldiisopropylsilyl group, a methyl di-t-butylsilyl group and atriisopropylsilyl group; tri-lower alkylsilyl groups substituted withone or two aryl groups such as a diphenylmethylsilyl group, abutyldiphenylbutylsilyl group, a diphenylisopropylsilyl group and aphenyldiisopropylsilyl group. Preferably the silyl group is atrimethylsilyl group, a triethylsilyl group, a triisopropylsilyl group,a t-butyldimethylsilyl group or a t-butyldiphenylsilyl group, morepreferably a trimethylsilyl group.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that withrespect to any molecule described as containing one or more optionalsubstituents, only sterically practical and/or synthetically feasiblecompounds are meant to be included. “Optionally substituted” refers toall subsequent modifiers in a term. So, for example, in the term“optionally substituted arylC₁₋₈ alkyl,” optional substitution may occuron both the “C₁₋₈ alkyl” portion and the “aryl” portion of the moleculemay or may not be substituted. A list of exemplary optionalsubstitutions is presented below in the definition of “substituted.”

“Optionally substituted alkyl” means an alkyl radical, as definedherein, optionally substituted with one or more group(s), specificallyone, two, three, four, or five groups, independently selected fromalkylcarbonyl, alkenylcarbonyl, cycloalkylcarbonyl, alkylcarbonyloxy,alkenylcarbonyloxy, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, cyano,cyanoalkylaminocarbonyl, alkoxy, alkenyloxy, hydroxy, hydroxyalkoxy,halo, carboxy, alkylcarbonylamino, alkylcarbonyloxy, alkyl-S(O)₀₋₂—,alkenyl-S(O)₀₋₂—, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, alkylsulfonyl-NR^(c)— (where R^(c) is hydrogen,alkyl, optionally substituted alkenyl, hydroxy, alkoxy, alkenyloxy, orcyanoalkyl), alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylaminoalkyloxy, dialkylaminoalkyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkoxycarbonylamino, alkylaminocarbonylamino,dialkylaminocarbonylamino, alkoxyalkyloxy, and —C(O)NR^(a)R^(b) (whereR^(a) and R^(b) are independently hydrogen, alkyl, optionallysubstituted alkenyl, hydroxy, alkoxy, alkenyloxy, or cyanoalkyl).

“Optionally substituted amino” refers to the group —N(H)R or —N(R)Rwhere each R is independently selected from the group: optionallysubstituted alkyl, optionally substituted alkoxy, optionally substitutedaryl, optionally substituted heterocycloalkyl, optionally substitutedheteroaryl, acyl, carboxy, alkoxycarbonyl, —S(O)₂-(optionallysubstituted alkyl), —S(O)₂-optionally substituted aryl),—S(O)₂-(optionally substituted heterocycloalkyl), —S(O)₂-(optionallysubstituted heteroaryl), and —S(O)₂-(optionally substituted heteroaryl).For example, “optionally substituted amino” includes diethylamino,methylsulfonylamino, and furanyl-oxy-sulfonamino.

“Optionally substituted aminoalkyl” means an alkyl group, as definedherein, substituted with at least one, specifically one or two,optionally substituted amino group(s), as defined herein.

“Optionally substituted aryl” means an aryl group, as defined herein,optionally substituted with one, two, or three substituentsindependently selected from acyl, acylamino, acyloxy, optionallysubstituted alkyl, optionally substituted alkenyl, alkoxy, alkenyloxy,halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino, alkylamino,dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “aryl”, the alkyl and alkenyl, either aloneor as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted arylalkyl” means an alkyl group, as definedherein, substituted with optionally substituted aryl, as defined herein.

“Optionally substituted cycloalkyl” means a cycloalkyl group, as definedherein, substituted with one, two, or three groups independentlyselected from acyl, acyloxy, acylamino, optionally substituted alkyl,optionally substituted alkenyl, alkoxy, alkenyloxy, alkoxycarbonyl,alkenyloxycarbonyl, alkylthio, alkylsulfinyl, alkylsulfonyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, halo, hydroxy, amino, alkylamino, dialkylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, nitro,alkoxyalkyloxy, aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,carboxy, and cyano. Within the above optional substituents on“cycloalkyl”, the alkyl and alkenyl, either alone or as part of anothersubstituent on the cycloalkyl ring, are independently optionallysubstituted with one, two, three, four, or five halo, e.g. haloalkyl,haloalkoxy, haloalkenyloxy, or haloalkylsulfonyl.

“Optionally substituted cycloalkylalkyl” means an alkyl groupsubstituted with at least one, specifically one or two, optionallysubstituted cycloalkyl groups, as defined herein.

“Optionally substituted heteroaryl” means a heteroaryl group optionallysubstituted with one, two, or three substituents independently selectedfrom acyl, acylamino, acyloxy, optionally substituted alkyl, optionallysubstituted alkenyl, alkoxy, alkenyloxy, halo, hydroxy, alkoxycarbonyl,alkenyloxycarbonyl, amino, alkylamino, dialkylamino, nitro,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, carboxy, cyano,alkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, alkylsulfonylamino,aminoalkoxy, alkylaminoalkoxy, and dialkylaminoalkoxy. Within theoptional substituents on “heteroaryl”, the alkyl and alkenyl, eitheralone or as part of another group (including, for example, the alkyl inalkoxycarbonyl), are independently optionally substituted with one, two,three, four, or five halo.

“Optionally substituted heteroarylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heteroaryl group(s), as defined herein.

“Optionally substituted heterocycloalkyl” means a heterocycloalkylgroup, as defined herein, optionally substituted with one, two, or threesubstituents independently selected from acyl, acylamino, acyloxy,optionally substituted alkyl, optionally substituted alkenyl, alkoxy,alkenyloxy, halo, hydroxy, alkoxycarbonyl, alkenyloxycarbonyl, amino,alkylamino, dialkylamino, nitro, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, carboxy, cyano, alkylthio, alkylsulfinyl,alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,alkylsulfonylamino, aminoalkoxy, or aryl is pentafluorophenyl. Withinthe optional substituents on “heterocycloalkyl”, the alkyl and alkenyl,either alone or as part of another group (including, for example, thealkyl in alkoxycarbonyl), are independently optionally substituted withone, two, three, four, or five halo.

“Optionally substituted heterocycloalkylalkyl” means an alkyl group, asdefined herein, substituted with at least one, specifically one or two,optionally substituted heterocycloalkyl group(s) as defined herein.

As used herein, “6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)” and“6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acid” refer to thesame chemical structure (3), as depicted below, and therefore they maybe used interchangeably.

More specifically, it is to be understood that for the purposes of thepresent invention, the terms “6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)calcium,” “6-(5-carboxy-5-methyl-hexyloxy)-2,2-dimethylhexanoic acidmonocalcium salt,” “CI-1027,” “gemcabene” (USAN nomenclature), and“compound 3” name the same chemical structure. Therefore, it is to beunderstood that the names may also be used interchangeably.

EMBODIMENTS

In one aspect, compounds of formula (III) and corresponding salts areprepared according to Scheme 1.

In Scheme 1, an ester of formula (I) is reacted with a deprotonatingreagent to produce an intermediate of formula (Ia).

In other aspects, the compound of formula (III) is hydrolyzed to producea compound of formula (V).

Esters of formula (I) are commercially available (Aldrich Chemical Co.,Milwaukee, Wis.). In some embodiments, an ester of formula (I) isprepared by well-known synthetic methods, for example, viaesterification of isobutyric acid (commercially available, AldrichChemical Co., Milwaukee, Wis.).

In some embodiments, R¹ is alkyl. More particularly, R¹ is C₁-C₈ alkyl.In other embodiments, R¹ is methyl or ethyl. More particularly, R¹ isethyl.

In some embodiments, R² and R³ are each independently selected fromalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, or heteroarylalkyl.In some embodiments, R² and R³ are selected from C₁-C₈ alkyl, C₃-C₆cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In one embodiment, R²and R³ are both C₁-C₈ alkyl. More particularly, R² and R³ are bothmethyl. In other embodiments, R² and R³ are both phenyl. In otherembodiments, R² is methyl and R³ is o-tolyl. In one embodiment, R² andR³ are the same. In other embodiments, R² and R³ are different.

In some embodiments, M¹ is an alkaline earth metal or alkali metal. Moreparticularly, M¹ is Ca or K.

In one embodiment, x is 1 or 2.

In some embodiments, n and m are each independently 0-4. In oneembodiment, R² and R³ are the same. In other embodiments, R² and R³ aredifferent. In one embodiment, n and m are independently 1 or 2. Inanother embodiment, n is 0 and m is 1. In another embodiment, n is 1 andm is 2. In another embodiment, n is 2 and m is 3. In another embodiment,n is 3 and m is 4. In another embodiment, both n and m are 0. In anotherembodiment, both n and m are 1. In another embodiment, both n and m are2. In another embodiment, both n and m are 3. In another embodiment,both n and m are 4.

In some embodiments, the deprotonating reagent is an organometallicreagent. More particularly, the organometallic reagent is (R)_(p)-M²,wherein M² is a metal, and p is the metal's valency value (1 for Li, 2for Zn, etc.). M² is selected from, for example, Zn, Na, Li, andGrignard reagents —Mg-Halo. More particularly, Halo is selected from thegroup consisting of iodo, bromo, and chloro.

In some embodiments, R is optionally substituted alkyl, optionallysubstituted cycloalkyl, optionally substituted cycloalkylalkyl,optionally substituted heterocycloalkyl, optionally substitutedheterocycloalkylalkyl, optionally substituted aryl, optionallysubstituted arylalkyl, optionally substituted heteroaryl, optionallysubstituted heteroarylalkyl, optionally substituted amino, optionallysubstituted alkylamino, optionally substituted aminoalkyl, optionallysubstituted dialkylamino, or optionally substituted alkylsilyl.

In one embodiment, the deprotonating agent is an alkylmetal base. Thealkylmetal base may be used a ratio from 0.5 eq to a slight equimolarexcess relative to the bis-halide of formula (2).

Organometallic reagents such as (R)_(p)— M² are commercially available(Aldrich Chemical Co., Milwaukee, Wis., FMC Lithium Lithco Product List,etc.). In some embodiments, organometallic reagents can be prepared bywell-known methods (Kharasch et al., Grignard Reactions of Non-MetallicSubstances; Prentice-Hall, Englewood Cliffs, N.J., pp. 138-528 (1954)and Hartley; Patai, The Chemistry of the Metal-Carbon Bond, Vol. 4,Wiley: New York, pp. 159-306 and pp. 162-175 (1989)).

In some embodiments, the reaction of an (R)_(p)-M² organometallicreagent with the ester of formula (I) to provide metal enolates, such aslithioenolates, can be performed using the general procedures describedin March, J. Advanced Organic Chemistry; Reactions Mechanisms, andStructure, 4th ed., 1992, pp. 920-929 and Eicher, Patai, The Chemistryof the Carbonyl Group, pt. 1, pp. 621-693; Wiley: New York, (1966). Inother embodiments, the synthetic procedure described in Comins, D. etal., Tetrahedron Lett. 1981, 22, 1085, can be used.

In one embodiment, the reaction is performed by adding an organicsolution of (R)_(p)-M² (approximately 0.5 to approximately 1.5 eq) to astirred, cooled (approximately 0° C. to approximately −80° C.) solutioncomprising an ester of formula (I). In some embodiments, this step isperformed under an inert atmosphere, such as nitrogen or argon gas. Moreparticularly, (R)_(p)-M² is added at such a rate that the temperature ofthe reaction mixture remains within approximately one to five degrees ofthe initial temperature of the ester of formula (I).

Non-limiting examples of suitable organometallic reagents include:

-   -   i. alkylmetal bases, such as methyllithium, n-butyllithium,        tert-butyllithium, sec butyllithium, phenyllithium, phenyl        sodium, phenyl potassium, n-hexyllithium, n heptyllithium, and        n-octyllithium;    -   ii. metal amide bases, such as lithium amide, sodium amide,        potassium amide, lithium tetramethylpiperidide, lithium        diisopropylamide, lithium diethylamide, lithium        dicyclohexylamide, sodium hexamethyldisilazide, and lithium        hexamethyldisilazide;    -   iii. hydride bases, such as sodium hydride and potassium        hydride;    -   iv. metal amide bases, such as lithium diisopropylamide; and    -   v. non-pyrophoric lithium derivatives, such as n-hexyllithium,        n-heptyllithium, and n-octyllithium.

More particularly, the organometallic reagent is selected fromn-butyllithium, n-hexyllithium, n-heptyllithium, and n-octyllithium inhexane solutions of various molar concentrations, but no less than 2M,commercially available in bulk quantities from commercial suppliers, forexample, Sigma-Aldrich FMC Lithium Lithco Product List.

In some embodiments, the process is used for large scale production ofcompounds of formula (III) or formula (V) and corresponding salts offormula (IV). In one embodiment, the organometallic reagent in the largescale process is selected from n-hexyllithium, n-heptyllithium, andn-octyllithium.

Suitable organic solvents for the reaction of the ester of formula (I)with the deprotonating agent include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, benzene,toluene, xylene, hydrocarbon solvents (such as pentane, hexane, andheptane), and mixtures thereof.

More particularly, in some embodiments, the organic solvent or mixtureof solvents is chosen in order to influence favorably to optimizeconversion to the lithioenolate by modulating the concentration of thelithium aggregate [(RLi)x(-LiX)y] formation, as described in Gossage, R.A. et al., Angew. Chem. Int. Ed. 2005, 44, 1448-1454. More particularly,the solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran,and mixtures thereof. In one embodiment, the lithium reagent/solventsystem in the large scale process is n-hexyllithium and hexane (SeeStouffer et al., U.S. Pat. No. 6,239,300).

In some embodiments, the reaction of the ester of formula (I) with thedeprotonating agent is performed in the presence of additives. Additivesmay be added, for example, to improve the selectivity of lithiation bybreaking up the lithium oligomers and stabilize the lithiatedintermediate. Particularly, solvents such as DMSO or chelating additivessuch as diamines, tetraalkylureas, and cyclic alkylureas, are used.Non-limiting examples of such chelating additives include, but are notlimited to, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),hexamethylphosphoramide (HMPA), N,N,N′,N′-tetramethylethylenediamine(TMEDA), and bis(N,N′-dimethylaminoethyl)ether. Exemplary procedures aredescribed in Wu, J.-P. et al., Tetrahedron Letters 2009, 50, 5667-5669(large scale lithiation using LDA and bis(N,N′-dimethylaminoethyl)ether)), van der Veen, R. H. et al., J. Org. Chem. 1985, 50, 342-346(for the LDA-HMPT reaction tandem), Dehmlow, E. V. et al., SyntheticCommunications 1998, 18, 487-494 (“Phase Transfer Catalytic Preparationof the Dipolar Aprotic Solvents DMI and DMPU”), Beck, A. K. et al.,“N,N′-Dimethylpropyleneurea”, in Encyclopedia of Reagents for OrganicSynthesis, New York: John Wiley & Sons, 2001, Mukhopadhyay, T. et al.,Helvetica ChimicaActa 1982, 65, 385-391 (“Substitution of HMPT by theCyclic Urea DMPU as a Cosolvent for highly Reactive Nucleophiles andBases”).

In some embodiments, the reaction of the ester of formula (I) with thedeprotonating agent can be performed by adding a solution comprising anester of formula (I) to a stirred, cooled organic solution(approximately 20° C. to approximately −80° C.) of (R)_(p)-M²(approximately 0.5 to approximately 1.5 eq). In some embodiments, thereaction is performed under an inert atmosphere, such as nitrogen orargon gas. Preferably, the solution comprising an ester of formula (I)is added at such a rate that the temperature of the reaction mixtureremains within approximately one to five degrees of the initialtemperature of the ester solution. An exemplary procedure, whichdescribes large scale metallations using n-butyllithium at lowtemperatures is published in Ashwood, M. S. et al., Organic ProcessResearch & Development 2004, 8, 192-200.

In one embodiment, the organic solvent is tetrahydrofuran,2-methyltetrahydrofuran, or mixtures thereof.

In another embodiment, the metallation reagent is selected from LDA,n-hexyllithium and n-heptyllithium.

Exemplary procedures in which the metallation agent is n-hexyllithiumare described in Baenziger, M. et al. Org. Proc. Res. Dev. 1997, 1, 395,Bishop, B. et al., US Pub no. 2006/0149069 A1 (WO2004078109), and Li, G.et al., US Pub. No. 2007/0105857 (WO2007044490). Exemplary procedures inwhich metallation reagents used are selected from n-hexyllithium andn-heptyllithium are found in Harmata, M. et al., Chem. Commun. 2003,2492-2493. See also Lochmann, L. et al., U.S. Pat. No. 3,971,816;Lipton, M. F. et al., Organic Process Research & Development 2003, 7,385-392, which describes preparations of lithioesters.

In all examples, the progress of the reaction can be followed using anappropriate analytical method, such as thin-layer chromatography orhigh-performance-liquid chromatography.

In some embodiments, after the deprotonation step, theα,ω-halo-terminated dialkane ether of formula (II) in an appropriatesolvent is added to the intermediate of formula (Ia) to provide acompound of formula (III). In some embodiments, the dialkane ether offormula (II) is added with cooling and stirring. More particularly, theaddition is performed at a rate such as the temperature variations areno more than five degrees of the initial temperature of the ester.

In some embodiments, the reaction mixture can be quenched with anaqueous solution (such as sodium chloride, ammonium chloride, etc.), andthe product can be isolated by typical workup methods. Suitable solventsfor solubilizing a compound of formula (III) include, but are notlimited to, dichloromethane, diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, benzene, toluene, xylene, hydrocarbon solvents(such as pentane, hexane, and heptane), and mixtures thereof.

In one embodiment, after the reaction is deemed substantially completeby using an appropriate analytical method, the reaction mixturecontaining the compound of formula (III) is hydrolyzed in the presenceof an alkaline earth metal salt or base, or oxide, or alkali metal saltor base. The salt formation is accomplished by treating the compound offormula (III) with an oxide, base, or salt in refluxing alcohols for 2to 96 hours. Typical examples include, but are not limited to,hydrolysis with K₂CO₃ in a refluxing mixture of DMSO and water. Furthersuitable procedures are referenced in Houben-Weyl, Methoden derOrganische Chemie, Georg Thieme Verlag Stuttgart 1964, vol. XII/2, pp.143-210 and 872-879, or Anderson, N. G., Practical Process Research &Development, Academic Press, London, 2000, pp. 93-94 and 181-182.

In yet another embodiment, the process comprises treating a solution ofa compound of formula (III) in a water-miscible solvent with an aqueoussolution of a base. More particularly, the water-miscible solvent isselected from DMF, DMSO, acetone, methanol, isopropyl alcohol, andethanol.

In yet another embodiment, the process comprises treating a solution ofthe compound of formula (III) in a water-immiscible solvent with anaqueous solution of a base. More particularly, the water-immisciblesolvent is selected from toluene, xylene, methyl ethyl ketone, andmethyl isobutyl ketone.

In yet another embodiment, the process comprises treating a solution ofthe compound of formula (III) in a water-miscible solvent with anaqueous solution of calcium hydroxide or calcium oxide. Moreparticularly, the water-miscible solvent is selected from DMF, DMSO,acetone, methanol, isopropyl alcohol, and ethanol.

In another embodiment, the process further comprises performing anaqueous work-up of the solution of step (b) in order to isolate anorganic fraction of the compound of formula (III).

In another embodiment, the process further comprises the step oftreating the crude compound of formula (III) with a hydroxide or oxideof an alkali or earth alkaline metal in a suitable solvent.

In another embodiment, the process further comprises the step ofprecipitating the salt of the α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV) in the presence of an organic solvent.

In another embodiment, the process further comprises the step ofremoving the organic layer by evaporation to afford crude crystallineα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV) asan alcohol solvate or hydrate.

In another embodiment, the process further comprises the step of addingone or more anti-solvents to the solid so that the salt of theα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV) isinsoluble.

In another embodiment, the process further comprises the step ofhumidifying the precipitate to obtain a crystalline salt ofα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV).

In a further embodiment, the process further comprises the preparationof a crystalline salt of a α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV) at multi-kilogram scale, wherein the processcomprises the steps of:

-   -   (a) reacting a solution comprising a substituted acetic acid        ester of formula (I) with a deprotonating reagent to produce an        intermediate of formula (Ia);    -   (b) reacting the intermediate of formula (Ia) with a solution        comprising a α,ω-halo-terminated dialkane ether of formula (II);    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of the compound of formula        (III);    -   (d) treating the crude compound of formula (III) of step (c)        with a hydroxide or oxide of an alkali or earth alkaline metal        in a suitable solvent;    -   (e) precipitating the salt of the α,ω-dicarboxylic        acid-terminated dialkane ether of formula (IV) in the presence        of an organic solvent; or, alternatively, removing the organic        layer by evaporation to afford crude crystalline        α,ω-dicarboxylic acid-terminated dialkane ether salt of        formula (IV) in the form of an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which the salt of the α,ω-dicarboxylic acid-terminated dialkane        ether of formula (IV) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain a crystalline salt of α,ω-dicarboxylic acid-terminated        dialkane ether of formula (IV).

In some embodiments, the metal salt of an α,ω-dicarboxylicacid-terminated dialkane ether of formula (IV) is isolated in a specificand consistently reproducible polymorph.

In a further embodiment, the process further comprises the preparationof a α,ω-dicarboxylic acid-terminated dialkane ether, wherein theprocess comprises the steps of:

-   -   (a) reacting a solution comprising a substituted acetic acid        ester of formula (I) with a deprotonating reagent to produce an        intermediate of formula (Ia);    -   (b) reacting the intermediate of formula (Ia) with a solution        comprising a α,ω-halo-terminated dialkane ether of formula (II);    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of the compound of formula        (III); and    -   (d) treating the crude compound of formula (III) of step (c)        with a hydroxide or oxide of an alkali or earth alkaline metal        in a suitable solvent.

In a further embodiment, the process further comprises the preparationof a crystalline salt of a α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV), wherein the process comprises the steps of:

-   -   (e) precipitating the salt of the α,ω-dicarboxylic        acid-terminated dialkane ether of formula (IV) in the presence        of an organic solvent; or, alternatively, removing the organic        layer by evaporation to afford crude crystalline        α,ω-dicarboxylic acid-terminated dialkane ether salt of        formula (IV) in the form of an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which the salt of the α,ω-dicarboxylic acid-terminated dialkane        ether of formula (IV) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain a crystalline salt of α,ω-dicarboxylic acid-terminated        dialkane ether of formula (IV).

In a particular embodiment, the invention provides a method for thepreparation of crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)calcium of formula (VIII), wherein the process comprises the steps of:

-   -   (a) reacting a solution of ethyl isobutyrate of formula (IXa)

with a deprotonating reagent to produce a compound of formula (X);

-   -   (b) reacting the ethyl lithiobutyrate of step (a) with a        solution of bis(4-chlorobutylether) of formula (XI);

-   -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3);

-   -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent;    -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4):

-   -   -   in the presence of an organic solvent, or, alternatively,            removing the organic layer by evaporation to afford crude            crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt            of formula (4) as an alcohol solvate or hydrate;

    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and

    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

In some embodiments, the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)calcium of formula (4) is isolated in a specific and consistentlyreproducible polymorph.

In a further embodiment, compounds of formula (3) and correspondingsalts (4) are prepared according to Scheme 2.

In a particular embodiment, the invention provides a method for thepreparation of a α,ω-dicarboxylic acid-terminated dialkane ether,wherein the process comprises the steps of:

-   -   (a) reacting a solution of ethyl isobutyrate of formula (IX)        with a deprotonating reagent;    -   (b) reacting the ethyl lithiobutyrate of step (a) with a        solution of bis(4-chlorobutylether) of formula (XI);    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3);    -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent.

In a further embodiment, the process further comprises the preparationof 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of formula (4),wherein the process comprises the steps of:

-   -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4) in the presence of an organic solvent;        or, alternatively, removing the organic layer by evaporation to        afford crude crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic        acid) salt of formula (4) as an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

In another aspect, compounds of formula (III) and corresponding saltsmay be prepared under certain conditions according to Scheme 3, whichutilizes a Reformatsky reaction. In Scheme 2, an α-bromoacetic acidester of formula (XV) is reacted with a bis(haloalkyl)ether of formula(II) and a metal to provide a compound of formula (III). Examples ofReformatsky reactions are described in Jun, I. Molecules 2012, 17,14249-14259. Exemplary procedures of Reformatsky reactions are collectedon-line, on the Organic Chemistry Portal atwww.organic-chemistry.org/namedreactions/reformatsky-reaction.shtm (lastvisited Nov. 12, 2014).

In other aspects, the compound of formula (III) is hydrolyzed to producea compound of formula (V).

In some embodiments of formula (V), R¹ is alkyl. More particularly, R¹is C1-C8 alkyl.

In other embodiments, R¹ is methyl or ethyl. More particularly, R¹ isethyl.

In some embodiments, R² and R³ are each independently alkyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, or heteroarylalkyl. In some embodiments, R² andR³ are selected from C₁-C₈ alkyl, C₃-C₆ cycloalkyl, heterocycloalkyl,aryl, or heteroaryl. In one embodiment, R² and R³ are both C₁-C₈ alkyl.More particularly, R² and R³ are both methyl. In other embodiments, R²and R³ are both phenyl. In other embodiments, R² is methyl and R³ iso-tolyl. In one embodiment, R² and R³ are the same. In otherembodiments, R² and R³ are different.

In some embodiments, x is 1 or 2.

In some embodiments, n and m are each independently 0-4. In oneembodiment, R² and R³ are the same. In other embodiments, R² and R³ aredifferent. In one embodiment, n and m are independently 1 or 2. Inanother embodiment, n is 0 and m is 1. In another embodiment, n is 1 andm is 2. In another embodiment, n is 2 and m is 3. In another embodiment,n is 3 and m is 4. In another embodiment, both n and m are 0. In anotherembodiment, both n and m are 1. In another embodiment, both n and m are2. In another embodiment, both n and m are 3. In another embodiment,both n and m are 4.

In some embodiments, M¹ is an alkaline earth metal or alkali metal. Moreparticularly, M¹ is Ca or K.

In one embodiment, the reaction is performed in the presence of a metalselected from zinc, magnesium, manganese, and indium. More particularly,the reaction is performed in the presence of zinc.

In one embodiment, the reaction is performed using a solvent selectedfrom toluene, xylene, ethers, tetrahydrofuran, diethyl ether, methylt-butyl ether, and 2-methyltetrahydrofuran.

In other embodiments, aqueous solutions of calcium or ammonium chloridecan be optionally used, as described in Bieber, L. W., J. Org. Chem.1997, 62, 9061-9064.

In some embodiments, initiators and/or catalysts are employed. Examplesof initiators and catalysts include, but are not limited to, iodine (seeZitsman, J. et al. Tetrahedron Letters 1971, 44, 4201-4204, and Johnson,P. Y. et al., J. Org. Chem. 1973, 38, 2346-2350). For MCPBA and MMPP seeBieber, L. W. J. Org. Chem. 1997, 62, 9061-9064.

In one embodiment, the α-bromoester of formula (XV) is cooled to −20° C.to 0° C. In some embodiments, the reaction is performed in an inertatmosphere, such as nitrogen or argon gas.

In some embodiments, the α-bromoester of formula (XV) is further treatedwith approximately 1 to 2.5 eq of a metal, more particularly 1 eq, in asolvent. More particularly, the solvent is tetrahydrofuran,2-methyltetrahydrofuran, or toluene.

In one example, the suspension is stirred until the metal is essentiallydissolved.

In one embodiment, if necessary, a catalyst is added as a reactioninitiator. The bis(halo)ether of formula (II) is then added at a flowrate that maintains the temperature between 0 and 10° C. duringaddition. Alternatively, the solution of the metallated α-bromoester offormula (XV) is added dropwise into the bis(halo)ether of formula (II)solution in an appropriate solvent.

The reaction mixture is then warmed to RT. If the reaction is notcomplete as determined by an appropriate analytical method the mixtureis then heated at 40 to 60° C. for several hours, particularly 50° C.for 4 hours.

In some embodiments, the reaction mixture is kept under vigorousstirring for several hours or up to 2 days until the conversion to thedesired product has ceased.

After the reaction is deemed substantially complete using an appropriateanalytical method, the reaction mixture containing the compound offormula (III) may be subjected to workup and extraction in an organicsolvent.

The crude product may be hydrolyzed in the presence of an alkaline earthmetal salt or base, oxide, or alkali metal salt or base to yield thediacid of formula (IV), as described for the examples in Scheme 2.

In some embodiments, the process further comprises performing an aqueouswork-up of the solution to isolate an organic fraction of the compoundof formula (III).

In one embodiment, the process further comprises the step of treatingthe crude compound of formula (III) with a hydroxide or oxide of analkali or earth alkaline metal in a suitable solvent.

In one embodiment, the process further comprises the step ofprecipitating the salt of the α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV) in the presence of an organic solvent.

In another embodiment, the process further comprises the step ofremoving the organic layer by evaporation to afford crude crystallineα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV) asan alcohol solvate or hydrate.

In one embodiment, the process further comprises the step of adding oneor more anti-solvents to the solid so that the salt of theα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV) isinsoluble.

In one embodiment, the process further comprises the step of humidifyingthe precipitate to obtain a crystalline salt of a α,ω-dicarboxylicacid-terminated dialkane ether of formula (IV).

In some embodiments, the process is used for large scale production ofcompounds of formula (III) or formula (V) and corresponding salts offormula (IV).

In yet another embodiment, the process comprises treating a solution ofa compound of formula (III) in a water-miscible solvent with an aqueoussolution of a base. More particularly, the water-miscible solvent isselected from DMF, DMSO, acetone, methanol, isopropyl alcohol, andethanol.

In yet another embodiment, the process comprises treating a solution ofthe compound of formula (III) in a water-immiscible solvent with anaqueous solution of a base. More particularly, the water-immisciblesolvent is selected from toluene, xylene, methyl ethyl ketone, andmethyl isobutyl ketone.

In yet another embodiment, the process comprises treating a solution ofthe compound of formula (III) in a water-miscible solvent with anaqueous solution of calcium hydroxide or calcium oxide. Moreparticularly, the water-miscible solvent is selected from DMF, DMSO,acetone, methanol, isopropyl alcohol, and ethanol.

In yet another embodiment, the process comprises treating a solution ofa compound of formula (III) in a water-immiscible solvent with anaqueous solution of calcium hydroxide or calcium oxide. Moreparticularly, the water-immiscible solvent is selected from toluene,xylene, methyl ethyl ketone, and methyl isobutyl ketone.

In a particular embodiment, the process for preparing the salt of acompound of formula (III) comprises:

-   -   (a) reacting a solution comprising an α-bromo-acetic acid ester        of formula (XV):

-   -   -   with a metal, until the metal is essentially dissolved;

    -   (b) reacting the solution of step (a) with a solution comprising        a α,ω-halo-terminated dialkane ether of formula (II)

-   -   -   wherein X is halo;

    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic fraction of the compound of formula        (III);

    -   (d) treating the crude compound of formula (III) of step (c)        with a hydroxide or oxide of an alkali or earth alkaline metal        in a suitable solvent;

    -   (e) precipitating the salt of the α,ω-dicarboxylic        acid-terminated dialkane ether of formula (IV) in the presence        of an organic solvent; or, alternatively, removing the organic        layer by evaporation to afford crude crystalline        α,ω-dicarboxylic acid-terminated dialkane ether salt of        formula (IV) as an alcohol solvate or hydrate;

    -   (f) adding one or more anti-solvents to the solid of step (e) in        which the salt of the α,ω-dicarboxylic acid-terminated dialkane        ether of formula (IV) is insoluble; and

    -   (g) humidifying the precipitate resultant from step (f) to        obtain a crystalline salt of a α,ω-dicarboxylic acid-terminated        dialkane ether of formula (IV).

In some embodiments, the α,ω-dicarboxylic acid-terminated dialkane etherof formula (IV) is isolated in a specific and consistently reproduciblepolymorph.

In a particular embodiment, the invention provides a method for thepreparation of a α,ω-dicarboxylic acid-terminated dialkane ether,wherein the process comprises the steps of:

-   -   (a) reacting a solution comprising an α-bromo-acetic acid ester        of formula (XV):

-   -   -   with a metal, until the metal is essentially dissolved;

    -   (b) reacting the solution of step (a) with a solution comprising        a α,ω-halo-terminated dialkane ether of formula (II)

-   -   -   wherein X is halo;

    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic fraction of the compound of formula        (III); and

    -   (d) treating the crude compound of formula (III) of step (c)        with a hydroxide or oxide of an alkali or earth alkaline metal        in a suitable solvent.

In one embodiment, the process for preparing a crystalline salt of aα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV)comprises:

-   -   (e) precipitating the salt of the α,ω-dicarboxylic        acid-terminated dialkane ether of formula (IV) in the presence        of an organic solvent; or, alternatively, removing the organic        layer by evaporation to afford crude crystalline        α,ω-dicarboxylic acid-terminated dialkane ether salt of        formula (IV) as an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which the salt of the α,ω-dicarboxylic acid-terminated dialkane        ether of formula (IV) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain a crystalline salt of a α,ω-dicarboxylic acid-terminated        dialkane ether of formula (IV).

In one embodiment, the process for the preparation of a crystalline formof 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of formula (4),wherein the process comprises the steps of:

-   -   (a) reacting a solution of an α-bromo-isobutyric acid ester of        formula (XX):

-   -   -   in a suitable solvent or mixture of solvents, under inert            atmosphere, with a metal, until the metal is essentially            dissolved;

    -   (b) reacting the solution of step (a) with a solution of        bis(4-chlorobutylether) of formula (XXI):

-   -   -   in a suitable solvent or mixture of solvents;

    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4);

-   -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent;    -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4)

-   -   -   in the presence of an organic solvent; or, alternatively,            removing the organic layer by evaporation to afford crude            crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt            of formula (4) as an alcohol solvate or hydrate;

    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and

    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

In a particular embodiment, the invention provides a method for thepreparation of a α,ω-dicarboxylic acid-terminated dialkane ether,wherein the process comprises the steps of:

-   -   (a) reacting a solution of an α-bromo-isobutyric acid ester of        formula (XX) in a suitable solvent or mixture of solvents, under        inert atmosphere, with a metal, until the metal is essentially        dissolved;    -   (b) reacting the solution of step (a) with a solution of        bis(4-chlorobutylether) of formula (XXI) in a suitable solvent        or mixture of solvents;    -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4);    -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent.

In a further embodiment, the process further comprises the preparationof 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of formula (4),wherein the process comprises the steps of:

-   -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4) in the presence of an organic solvent;        or, alternatively, removing the organic layer by evaporation to        afford crude crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic        acid) salt of formula (4) as an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

A further aspect is a process for preparing a compound of formula (48)using a Williamson ether synthesis:

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a first solution of a compound of formula (46):

with a halogen source to produce a compound of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (b) reacting a second solution of a compound of formula (46)        with the intermediate of formula (37) in the presence of base to        form a compound of formula (48).

In some embodiments, step (a) is in the presence of triphenylphosphine.

A further aspect is a process for preparing a compound of formula (48a)using a Williamson ether synthesis:

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m and n are each in is 0-4;        comprising:    -   (a) reacting a solution of a compound of formula (46a):

with a halogen source to produce a compound of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (b) reacting a solution of a compound of formula (46b):

-   -   with the intermediate of formula (47) in the presence of base to        form a compound of formula (48a).

In some embodiments, the compound of formula (46a) is different than thecompound of formula (46b). In some embodiments, the compound of formula(46a) is the same as compound (46b).

Some embodiments further comprise the step of reacting the solution of acompound of formula (45):

with potassium tert-butoxide to produce an intermediate of formula (46).

Some embodiments further comprise the step of reacting an intermediateof formula (43a):

wherein M²³ is Li or Zn;with a solution of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;to produce a compound of formula (45).

Some embodiments further comprise the step of reacting the solution of acompound of formula (43):

with a deprotonating reagent to produce an intermediate of formula(43a).

Some embodiments further comprise the step of reacting the intermediateof formula (41a):

wherein M²² is Li or Zn;with a solution of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;to produce a compound of formula (43).

Some embodiments further comprise the step of reacting a solution of acyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a).

Some embodiments further comprise the step of hydrolyzing the compoundof formula (48) to produce a compound of formula (49).

In some embodiments, the compound of formula (48) is the di-tert-butylester of 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid) (14).

Another aspect is a process for preparing a compound of formula (49):

wherein:

-   -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45):

-   -   (e) reacting the solution of a compound of formula (45) with        potassium tert-butoxide to produce an intermediate of formula        (46):

wherein R²¹ is tert-butyl;

-   -   (f) reacting the solution of a compound of formula (46) with a        halogen source to produce an intermediate of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting the solution of a compound of formula (46) with the        intermediate of formula (47) in the presence of base to form a        compound of formula (48):

-   -   (h) reacting the solution of a compound of formula (48) with        dilute acid to form 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid)        (49).

In some embodiments, step (f) is performed in the presence oftriphenylphosphine, SOCl₂ or SOBr₂ in pyridine or trialkylamine, orphosphorus (III) bromide or iodide.

More particularly, in one embodiment, step (f) is carried out in thepresence of triphenylphosphine.

Some embodiments further comprise the step of:

-   -   (i) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (49) of        step (h) with a calcium hydroxide or calcium oxide of an alkali        or earth alkaline metal in a suitable solvent.

Some embodiments further comprise the step of:

-   -   (j) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (50):

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt of        formula (50) as an alcohol solvate or hydrate.

Some embodiments further comprise the step of:

-   -   (k) adding one or more anti-solvents to the solid of step (j) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (50) is insoluble.

Some embodiments further comprise the step of:

-   -   (l) humidifying the precipitate resultant from step (k) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (50).

Another aspect is a process for preparing a compound of formula (48):

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl;    -   m and n are each independently 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45):

-   -   (e) reacting the solution of a compound of formula (45) with        potassium tert-butoxide to produce an intermediate of formula        (46):

where R²¹ is alkyl;

-   -   (f) reacting the solution of a compound of formula (46) with a        halogen source to produce an intermediate of formula (47):

wherein X²⁴ is F, Cl, or I and where R²¹ is alkyl;

-   -   (g) reacting a solution of the compound of formula (46) with the        intermediate of formula (47) in the presence of base to form a        compound of formula (48).

In some embodiments, step (f) is in the presence of triphenylphosphine.

Another embodiment further comprises the step of performing an aqueouswork-up of the solution of step (b) to isolate an organic solution ofthe compound of formula (43).

Another embodiment further comprises the step of performing an aqueouswork-up of the solution of step (d) to isolate an organic solution ofthe compound of formula (45).

Another embodiment further comprises the step of performing an aqueouswork-up of the solution of step (e) to isolate an organic solution ofthe compound of formula (46).

Another embodiment further comprises the step of performing an aqueouswork-up of the solution of step (f) to isolate an organic solution ofthe compound of formula (47).

Another embodiment further comprises the step of hydrolyzing thecompound of formula (48) to produce a compound of formula (49).

Another embodiment further comprises treating a solution of a compoundof formula (48) with dilute acid.

Some embodiments further comprise treating a solution of a compound offormula (48) in a water-immiscible solvent with dilute acid, wherein thewater-immiscible solvent is selected from dichloromethane, diethylether, tetrahydrofuran, 2-methyltetrahydrofuran, benzene, toluene,xylene, hydrocarbon solvents such as pentane, hexane, and heptane, andmixtures thereof.

Another embodiment further comprises treating a solution of a compoundof formula (48) with a dilute acid selected from the group consisting oftrifluoroacetic acid, formic acid, hydrochloric acid, and sulfuric acid.

Another embodiment further comprises the step of performing an aqueouswork-up of the solution of step (g) to isolate an organic solution ofthe compound of formula (48).

In some embodiments, X²² and X²³ are each independently F, Cl, or I.

In some embodiments, R²¹ is tert-butyl.

In some embodiments, R²² is methyl, ethyl, or methylphenyl.

In some embodiments, R²² is methyl.

In some embodiments, R²³ is methyl, ethyl, or methylphenyl.

In some embodiments, R²³ is methyl.

In another embodiment, the compound of formula (48) is the di-tert-butylester of 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

Another aspect is a process for preparing6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

comprising:

-   -   (a) reacting a solution of a cyclic lactone:

with a deprotonating reagent to produce an intermediate:

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of step (a) with a solution of an        alkylhalide

H₃C—X²²   52

wherein X²² is halo;

to produce a compound:

-   -   (c) reacting the solution of the compound of step (b) with a        deprotonating reagent to produce an intermediate:

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of step (c) with a solution of an        alkylhalide:

H₃C—X²³   54

wherein X²³ is halo;

to produce a compound:

-   -   (e) reacting the solution of a compound of step (d) with        potassium tert-butoxide to produce an intermediate:

-   -   (f) reacting a first solution of a compound of step (e) with a        halogen source to produce an intermediate:

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting a second solution of a compound of step (e) with        the intermediate of step (f)) in the presence of base to form a        compound:

-   -   (h) reacting the solution of a compound of step (g) with dilute        acid to form 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

A further aspect is a process for preparing crystalline6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium:

wherein the process comprises:

-   -   (a) reacting a solution of a cyclic lactone:

with a deprotonating reagent to produce an intermediate:

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of step (a) with a solution of an        alkylhalide

H₃C—X²²   52

wherein X²² is halo;

to produce a compound:

-   -   (c) reacting the solution of the compound of step (b) with a        deprotonating reagent to produce an intermediate:

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of step (c) with a solution of an        alkylhalide:

H₃C—X²³   54

wherein X²³ is halo;

to produce a compound:

-   -   (e) reacting the solution of a compound of step (d) with        potassium tert-butoxide to produce an intermediate:

-   -   (f) reacting a first solution of a compound of step (e) with a        halogen source to produce an intermediate:

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting a second solution of a compound of step (e) with        the intermediate of step (f)) in the presence of base to form a        compound:

-   -   (h) reacting the solution of a compound of step (g) with dilute        acid to form 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

-   -   (i) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of step (h) with a calcium        hydroxide or calcium oxide of an alkali or earth alkaline metal        in a suitable solvent;    -   (j) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of step (i)

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt as an        alcohol solvate or hydrate;    -   (k) adding one or more anti-solvents to the solid of step (j) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium is        insoluble; and    -   (l) humidifying the precipitate resultant from step (k) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium.

In some embodiments, step (f) is in the presence of triphenylphosphine.

In some embodiments, the alcohol solvate or hydrate obtained in step (j)is stirred with tetrahydrofuran with subsequent addition of one or moreanti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (k).

A further aspect is a process for preparing a compound of formula (45):

wherein:

-   -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45).

In some embodiments, m is 1.

In some embodiments, R²² and R²³ are the same. In other embodiments, R²³and R²² are different.

ADDITIONAL EMBODIMENTS Embodiment 1

A process for preparing a compound of formula (III):

wherein:

R¹ is alkyl;

R² and R³ are each independently alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl; and

n and m are each independently 0-4;

comprising:

-   -   (a) reacting a solution comprising a substituted acetic acid        ester of formula (I):

with a deprotonating reagent to produce an intermediate of formula (Ia):

wherein M² is Li or Zn; and

-   -   (b) reacting the intermediate of formula (Ia) with a solution        comprising a α,ω-halo-terminated dialkane ether of formula (II)

wherein X is halo;

to produce a compound of formula (III).

Embodiment 2

The process of embodiment 1, further comprising the step of performingan aqueous work-up of the solution of step (b) to isolate an organicsolution of the compound of formula (III).

Embodiment 3

The process of any of embodiments 1-2, further comprising the step oftreating the crude compound of formula (III) with an aqueous solution ofa hydroxide or oxide of an alkali or earth alkaline metal.

Embodiment 4

The process of any of embodiments 1-3, further comprising the step ofprecipitating the salt of the α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV) in the presence of an organic solvent.

Embodiment 5

The process of any of embodiments 1-4, further comprising the step ofremoving the organic layer by evaporation to afford crude crystallineα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV) inthe form of an alcohol solvate or hydrate.

Embodiment 6

The process of any of embodiments 1-5, wherein the alcohol solvate orhydrate is stirred with tetrahydrofuran with subsequent addition of oneor more anti-solvents to obtain the crystalline form theα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV).

Embodiment 7

The process of any of embodiments 1-6, further comprising the step ofadding one or more anti-solvents so that the salt of theα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV) isinsoluble.

Embodiment 8

The process of any of embodiments 1-7, further comprising the step ofhumidifying the precipitate to obtain a crystalline salt of aα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV).

Embodiment 9

The process of any of embodiments 1-8, further comprising the step ofhydrolyzing the compound of formula (III) to produce a compound offormula (V).

Embodiment 10

The process of any of embodiments 1-9, comprising treating a solution ofa compound of formula (III) in a water-miscible solvent with an aqueoussolution of a base, wherein the water-miscible solvent is selected fromDMSO, DMF, methanol, isopropyl alcohol, and ethanol.

Embodiment 11

The process of any of embodiments 1-10, comprising treating a solutionof a compound of formula (III) in a water-immiscible solvent with anaqueous solution of a base, wherein the water-immiscible solvent isselected from toluene, xylene, methyl ethyl ketone, and methyl isobutylketone.

Embodiment 12

The process of any of embodiments 1-11, comprising treating a solutionof a compound of formula (III) in a water-miscible solvent with anaqueous solution of calcium hydroxide or calcium oxide, wherein thewater-miscible solvent is selected from DMSO, DMF, acetone, methanol,isopropyl alcohol, and ethanol.

Embodiment 13

The process of any of embodiments 1-12, comprising treating a solutionof a compound of formula (III) in a water-immiscible solvent with anaqueous solution of calcium hydroxide or calcium oxide, wherein thewater-immiscible solvent is selected from toluene, xylene, methyl ethylketone, and methyl isobutyl ketone.

Embodiment 14

The process of any of embodiments 1-13, wherein step (a) is performedunder inert atmosphere.

Embodiment 15

The process of any of embodiments 1-14, wherein the deprotonatingreagent is selected from hexyllithium and heptyllithium.

Embodiment 16

The process of any of embodiments 1-15, wherein the solvent in step (a)is selected from dichloromethane, diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, dimethylformamide, dimethyl sulfoxide, benzene,toluene, xylene, hydrocarbon solvents such as pentane, hexane, andheptane, and mixtures thereof.

Embodiment 17

The process of any of embodiments 1-16, wherein the solvent in step (b)is dichloromethane, diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, benzene, toluene, xylene, hydrocarbon solventssuch as pentane, hexane, and heptane, and mixtures thereof.

Embodiment 18

The process of any of embodiments 1-17, wherein X is F, Cl, or I.

Embodiment 19

The process of any of embodiments 1-18, wherein X is Cl.

Embodiment 20

The process of any of embodiments 1-19, wherein R¹ is methyl or ethyl.

Embodiment 21

The process of any of embodiments 1-20, wherein R¹ is ethyl.

Embodiment 22

The process of any of embodiments 1-21, wherein R² is methyl, ethyl, orphenyl.

Embodiment 23

The process of any of embodiments 1-22, wherein R² is methyl.

Embodiment 24

The process of any of embodiments 1-23, wherein R³ is methyl, ethyl, orphenyl.

Embodiment 25

The process of any of embodiments 1-24, wherein R³ is methyl.

Embodiment 26

The process of any of embodiments 1-25, wherein n and m are the same.

Embodiment 27

The process of any of embodiments 1-26, wherein n and m are different.

Embodiment 28

The process of any of embodiments 1-27, wherein n and m are each 1.

Embodiment 29

The process of any of embodiments 1-28, wherein the compound of formula(III) is 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid) (Compound 3).

Embodiment 30

A process for preparing 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

comprising:

-   -   (a) reacting a solution comprising a substituted acetic acid        ester of formula (IXa):

with a deprotonating reagent to produce an intermediate of formula (X):

wherein M² is Li or Zn;

-   -   (b) reacting the intermediate of formula (X) with a solution        comprising a α,ω-halo-terminated dialkane ether of formula (XI)

wherein X is halo; and L

-   -   (c) hydrolyzing the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate);    -   to produce 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

Embodiment 31

A process for preparing crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoicacid) calcium of formula (4):

wherein the process comprises:

-   -   (a) reacting a solution of ethyl isobutyrate of formula (IX)

with a deprotonating reagent to produce a compound of formula (X);

-   -   (b) reacting the ethyl lithiobutyrate of step (a) with a        solution of bis(4-chlorobutylether) of formula (XI);

-   -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3);

-   -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent;    -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4):

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt of        formula (4) as an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

Embodiment 32

The process of embodiment 31, wherein the alcohol solvate or hydrateobtained in step (f) is stirred with tetrahydrofuran with subsequentaddition of one or more anti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (g).

Embodiment 33

The process of any of embodiments 31-32, wherein the solid obtainedaccording to step (d) is stirred with tetrahydrofurane with subsequentaddition of one or more anti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (g).

Embodiment 34

The process of any of embodiments 31-32, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) in awater-immiscible solvent with an aqueous solution of a base, wherein thewater-miscible solvent is selected from DMSO, DMF, acetone, methanol,isopropyl alcohol, and ethanol.

Embodiment 35

The process of any of embodiments 31-32, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) in awater-immiscible solvent with an aqueous solution of a base, wherein thewater-immiscible solvent is selected from toluene, xylene, methyl ethylketone, and methyl isobutyl ketone.

Embodiment 36

The process of any of embodiments 31-32, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) in awater-miscible solvent with an aqueous solution of calcium hydroxide orcalcium oxide, wherein the water-miscible solvent is selected from DMSO,DMF, acetone, methanol, isopropyl alcohol, and ethanol.

Embodiment 37

The process of any of embodiments 31-32, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (3) in awater-immiscible solvent with an aqueous solution of a calcium hydroxideor calcium oxide, wherein the water-immiscible solvent is selected fromtoluene, xylene, methyl ethyl ketone, and methyl isobutyl ketone.

Embodiment 38

A process for preparing a compound of formula (III):

wherein:

R¹ is alkyl;

R² and R³ are each independently alkyl, cycloalkyl, cycloalkylalkyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, orheteroarylalkyl; and

n and m are each independently 0-4;

comprising:

-   -   (a) reacting a solution comprising an α-bromo-acetic acid ester        of formula (XV):

with a metal, until the metal is essentially dissolved;

-   -   (b) reacting the solution of step (a) with a solution comprising        a α,ω-halo-terminated dialkane ether of formula (II):

wherein X is halo;

to produce a compound of formula (III).

Embodiment 39

The process of embodiment 38, further comprising the step of performingan aqueous work-up of the solution of step (b) to isolate an organicsolution of the compound of formula (III).

Embodiment 40

The process of any of embodiments 38-39, further comprising the step oftreating the crude compound of formula (III) with a hydroxide or oxideof an alkali or earth alkaline metal.

Embodiment 41

The process of any of embodiments 38-40, further comprising the step ofprecipitating the salt of the α,ω-dicarboxylic acid-terminated dialkaneether of formula (IV) in the presence of an organic solvent.

Embodiment 42

The process of any of embodiments 38-41, further comprising the step ofremoving the organic layer by evaporation to afford crude crystallineα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV) inthe form of an alcohol solvate or hydrate.

Embodiment 43

The process of any of embodiments 38-42, wherein the alcohol solvate orhydrate is stirred with tetrahydrofuran with subsequent addition of oneor more anti-solvents to obtain the crystalline form theα,ω-dicarboxylic acid-terminated dialkane ether salt of formula (IV).

Embodiment 44

The process of any of embodiments 38-43, further comprising the step ofadding one or more anti-solvents so that the salt of theα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV) isinsoluble.

Embodiment 45

The process of any of embodiments 38-44, further comprising the step ofhumidifying the precipitate to obtain a crystalline salt of aα,ω-dicarboxylic acid-terminated dialkane ether of formula (IV).

Embodiment 46

The process of embodiment 38-45, further comprising the step ofhydrolyzing the compound of formula (III) to produce a compound offormula (V).

Embodiment 47

The process of any of embodiments 38-46, comprising treating a solutionof a compound of formula (III) in a water-miscible solvent with anaqueous solution of a base, wherein the water-miscible solvent isselected from DMSO, DMF, methanol, isopropyl alcohol, and ethanol.

Embodiment 48

The process of any of embodiments 38-47, comprising treating a solutionof a compound of formula (III) in a water-immiscible solvent with anaqueous solution of a base, wherein the water-immiscible solvent isselected from toluene, xylene, methyl ethyl ketone, and methyl isobutylketone.

Embodiment 49

The process of any of embodiments 38-48, comprising treating a solutionof a compound of formula (III) in a water-miscible solvent with anaqueous solution of calcium hydroxide or calcium oxide, wherein thewater-miscible solvent is selected from DMSO, DMF, acetone, methanol,isopropyl alcohol, and ethanol.

Embodiment 50

The process of any of embodiments 38-49, comprising treating a solutionof a compound of formula (III) in a water-immiscible solvent with anaqueous solution of calcium hydroxide or calcium oxide, wherein thewater-immiscible solvent is selected from toluene, xylene, methyl ethylketone and methyl isobutyl ketone.

Embodiment 51

The process of any of embodiments 38-50, wherein step (a) is performedunder inert atmosphere.

Embodiment 52

The process of any of embodiments 38-51, wherein the deprotonatingreagent is selected from alkyl-lithium, aryl-lithium, dialkyl-zinc, oralkali metal salts of hexamethyldisililazanes.

Embodiment 53

The process of any of embodiments 38-52, wherein the solvent in step (a)is selected from tetrahydrofuran, 2-methyltetrahydrofuran, or toluene.

Embodiment 54

The process of any of embodiments 38-53, wherein X is F, Cl, or I.

Embodiment 55

The process of any of embodiments 38-54, wherein X is Cl.

Embodiment 56

The process of any of embodiments 38-55, wherein R¹ is methyl or ethyl.

Embodiment 57

The process of any of embodiments 38-56, wherein R¹ is ethyl.

Embodiment 58

The process of any of embodiments 38-57, wherein R² is methyl, ethyl, orphenyl.

Embodiment 59

The process of any of embodiments 38-58, wherein R² is methyl.

Embodiment 60

The process of any of embodiments 38-59, wherein R³ is methyl, ethyl, orphenyl.

Embodiment 61

The process of any of embodiments 38-60, wherein R³ is methyl.

Embodiment 62

The process of any of embodiments 38-61, wherein n and m are the same.

Embodiment 63

The process of any of embodiments 38-62, wherein n and m are different.

Embodiment 64

The process of any of embodiments 38-63, wherein n and m are each 1.

Embodiment 65

The process of any of embodiments 38-64, wherein the metal is selectedfrom the group consisting of zinc, magnesium and indium.

Embodiment 66

The process of any of embodiments 38-65, wherein catalysts or initiatorsare optionally used in step (a).

Embodiment 67

The process of any of embodiments 38-66, wherein catalysts or initiatorsare selected from the group consisting of benzoyl peroxide,3-chloroperbenzoic acid or magnesium monoperoxyphthalate.

Embodiment 68

The process of any of embodiments 38-67, wherein the compound of formula(III) is 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid) (Compound 3).

Embodiment 69

A process for preparing 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

comprising:

-   -   (a) reacting a solution comprising an α-bromo-acetic acid ester        of formula (XX):

with a metal, until the metal is essentially dissolved;

-   -   (b) reacting the solution of step (a) with a solution comprising        a α,ω-halo-terminated dialkane ether of formula (XXI):

wherein X is halo; and

-   -   (c) hydrolyzing the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate); to produce        6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

Embodiment 70

A process for preparing crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoicacid) calcium of formula (4):

wherein the process comprises:

-   -   (a) reacting a solution of an α-bromo-isobutyric acid ester of        formula (XX):

-   -   in a suitable solvent or mixture of solvents, under inert        atmosphere, with a metal, until the metal is essentially        dissolved;    -   (b) reacting the solution of step (a) with a solution of        bis(4-chlorobutylether) of formula (XXI):

in a suitable solvent or mixture of solvents;

-   -   (c) performing an aqueous work-up of the solution of step (b) in        order to isolate an organic solution of crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula 4;

-   -   (d) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) of step (c)        with a calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent;    -   (e) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4):

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt of        formula (4) as an alcohol solvate or hydrate;    -   (f) adding one or more anti-solvents to the solid of step (e) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (4) is insoluble; and    -   (g) humidifying the precipitate resultant from step (f) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (4).

Embodiment 71

The process of embodiment 70, wherein the alcohol solvate or hydrateobtained in step (f) is stirred with tetrahydrofuran with subsequentaddition of one or more anti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (g).

Embodiment 72

The process of any of embodiments 70-71, wherein the solid obtainedaccording to step (d) is stirred with tetrahydrofurane with subsequentaddition of one or more anti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (g).

Embodiment 73

The process of any of embodiments 70-72, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) in a in awater-miscible solvent with an aqueous solution of a base, wherein thewater-miscible solvent is selected from DMSO, DMF, acetone, methanol,isopropyl alcohol, and ethanol

Embodiment 74

The process of any of embodiments 70-72, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) in awater-immiscible solvent with an aqueous solution of a base, wherein thewater-immiscible solvent is selected from toluene, xylene, methyl ethylketone, and methyl isobutyl ketone.

Embodiment 75

The process of any of embodiments 70-72, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) in awater-miscible solvent with an aqueous solution of calcium hydroxide orcalcium oxide, wherein the water-miscible solvent is selected from DMSO,DMF, acetone, methanol, isopropyl alcohol, and ethanol.

Embodiment 76

The process of any of embodiments 70-72, comprising treating a solutionof ethyl 6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (4) in awater-immiscible solvent with an aqueous solution of calcium hydroxideor calcium oxide, wherein the water-immiscible solvent is selected fromtoluene, xylene, methyl ethyl ketone, and methyl isobutyl ketone.

Embodiment 77

A process for preparing a compound of formula (48):

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45):

-   -   (e) reacting the solution of a compound of formula (45) with        potassium tert-butoxide to produce an intermediate of formula        (46):

where R²¹ is alkyl;

-   -   (f) reacting the solution of a compound of formula (46) with a        halogen source to produce an intermediate of formula (47):

wherein X²⁴ is F, Cl, or I and where R²¹ is alkyl;

-   -   (g) reacting a solution of the compound of formula (46) with the        intermediate of formula (47) in the presence of base to form a        compound of formula (48).

Embodiment 78

The process of embodiment 77, further comprising the step of performingan aqueous work-up of the solution of step (b) to isolate an organicsolution of the compound of formula (43).

Embodiment 79

The process of any of embodiments 77-78, further comprising the step ofperforming an aqueous work-up of the solution of step (d) to isolate anorganic solution of the compound of formula (45).

Embodiment 80

The process of any of embodiments 77-79, further comprising the step ofperforming an aqueous work-up of the solution of step (e) to isolate anorganic solution of the compound of formula (46).

Embodiment 81

The process of any of embodiments 77-80, further comprising the step ofperforming an aqueous work-up of the solution of step (f) to isolate anorganic solution of the compound of formula (47).

Embodiment 82

The process of any of embodiments 77-81, further comprising the step ofhydrolyzing the compound of formula (48) to produce a compound offormula (49).

Embodiment 83

The process of any of embodiments 77-82, comprising treating a solutionof a compound of formula (48) with dilute acid.

Embodiment 84

The process of any of embodiments 77-83, comprising treating a solutionof a compound of formula (48) in a water-immiscible solvent with diluteacid, wherein the water-immiscible solvent is selected fromdichloromethane, diethyl ether, tetrahydrofuran,2-methyltetrahydrofuran, benzene, toluene, xylene, hydrocarbon solventssuch as pentane, hexane, and heptane, and mixtures thereof.

Embodiment 85

The process of any of embodiments 77-84, comprising treating a solutionof a compound of formula (48) with a dilute acid selected from the groupconsisting of trifluoroacetic acid, formic acid, hydrochloric acid, andsulfuric acid.

Embodiment 86

The process of any of embodiments 77-85, further comprising the step ofperforming an aqueous work-up of the solution of step (g) to isolate anorganic solution of the compound of formula (48).

Embodiment 87

The process of any of embodiments 77-86, wherein X²² and X²³ are eachindependently F, Cl, or I.

Embodiment 88

The process of any of embodiments 77-87, wherein R²¹ is tert-butyl.

Embodiment 89

The process of any of embodiments 77-88, wherein R²² is methyl, ethyl,or methylphenyl.

Embodiment 90

The process of any of embodiments 77-89, wherein R²² is methyl.

Embodiment 91

The process of any of embodiments 77-90, wherein R²³ is methyl, ethyl,or methylphenyl.

Embodiment 92

The process of any of embodiments 77-91, wherein R²³ is methyl.

Embodiment 93

The process of any of embodiments 77-92, wherein the compound of formula(38) is the di-tert-butyl ester of 6,6′-oxy-bis(2,2-dimethyl-4-hexanoicacid).

Embodiment 94

A process for preparing 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

comprising:

-   -   (a) reacting a solution of a cyclic lactone:

with a deprotonating reagent to produce an intermediate:

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of step (a) with a solution of an        alkylhalide

H₃C—X²²   52

wherein X²² is halo;

to produce a compound:

-   -   (c) reacting the solution of the compound of step (b) with a        deprotonating reagent to produce an intermediate:

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of step (c) with a solution of an        alkylhalide:

H₃C—X²³   54

wherein X²³ is halo;

to produce a compound:

-   -   (e) reacting the solution of a compound of step (d) with        potassium tert-butoxide to produce an intermediate:

-   -   (f) reacting a first solution of a compound of step (e) with a        halogen source to produce an intermediate:

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting a second solution of a compound of step (e) with        the intermediate of step (f)) in the presence of base to form a        compound:

-   -   (h) reacting the solution of a compound of step (g) with dilute        acid to form 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

Embodiment 95

A process for preparing crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoicacid) calcium (4):

wherein the process comprises:

-   -   (a) reacting a solution of a cyclic lactone:

with a deprotonating reagent to produce an intermediate:

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of step (a) with a solution of an        alkylhalide

H₃C—X²²   52

wherein X²² is halo;

to produce a compound:

-   -   (c) reacting the solution of the compound of step (b) with a        deprotonating reagent to produce an intermediate:

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of step (c) with a solution of an        alkylhalide:

H₃C—X²³   54

wherein X²³ is halo;

to produce a compound:

-   -   (e) reacting the solution of a compound of step (d) with        potassium tert-butoxide to produce an intermediate:

-   -   (f) reacting a first solution of a compound of step (e) with a        halogen source to produce an intermediate:

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting a second solution of a compound of step (e) with        the intermediate of step (f)) in the presence of base to form a        compound:

-   -   (h) reacting the solution of a compound of step (g) with dilute        acid to form 6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid):

-   -   (i) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of step (h) with a calcium        hydroxide or calcium oxide of an alkali or earth alkaline metal        in a suitable solvent;    -   (j) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of step (i)

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt as an        alcohol solvate or hydrate;    -   (k) adding one or more anti-solvents to the solid of step (j) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium is        insoluble; and    -   (l) humidifying the precipitate resultant from step (k) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium (4).

Embodiment 96

The process of embodiment 95, wherein the alcohol solvate or hydrateobtained in step (j) is stirred with tetrahydrofuran with subsequentaddition of one or more anti-solvents to obtain the crystalline form of6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium described in step (k).

Embodiment 97

A process for preparing a compound of formula (48):

wherein:

-   -   R²¹ is alkyl;    -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a first solution of a compound of formula (46):

with a halogen source to produce a compound of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (b) reacting a second solution of a compound of formula (46)        with the intermediate of formula (47) in the presence of base to        form a compound of formula (48).

Embodiment 98

The process of embodiment 97, further comprising the step of reactingthe solution of a compound of formula (45):

with potassium tert-butoxide to produce an intermediate of formula (46).

Embodiment 99

The process of embodiments 97-98, further comprising the step ofreacting an intermediate of formula (43a):

wherein M²³ is Li or Zn;with a solution of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;to produce a compound of formula (45).

Embodiment 100

The process of embodiments 97-99, further comprising the step ofreacting the solution of a compound of formula (43):

with a deprotonating reagent to produce an intermediate of formula(43a).

Embodiment 101

The process of embodiments 97-100, further comprising the step ofreacting the intermediate of formula (41a):

wherein M²² is Li or Zn;with a solution of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;to produce a compound of formula (43).

Embodiment 102

The process of embodiments 97-101, further comprising the step ofreacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a).

Embodiment 103

The process of any of embodiments 97-102, further comprising the step ofhydrolyzing the compound of formula (48) to produce a compound offormula (49).

Embodiment 104

The process of any of embodiments 97-103, wherein the compound offormula (38) is the di-tert-butyl ester of6,6′-oxy-bis(2,2-dimethyl-4-hexanoic acid).

Embodiment 105

A process for preparing a compound of formula (45):

comprising:

-   -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45).

Embodiment 106

The process of any of embodiments 97-103, further comprising the stepsof:

-   -   (e) treating the crude diethyl        6,6′-oxybis(2,2-dimethyl-4-hexanoate) of formula (49) of        step (h) with a calcium hydroxide or calcium oxide of an alkali        or earth alkaline metal in a suitable solvent;    -   (f) precipitating the 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (50):

-   -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford crude        crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) salt of        formula (50) as an alcohol solvate or hydrate;    -   (g) adding one or more anti-solvents to the solid of step (j) in        which 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid) calcium of        formula (50) is insoluble; and    -   (h) humidifying the precipitate resultant from step (k) to        obtain crystalline 6,6′-oxybis(2,2-dimethyl-4-hexanoic acid)        calcium of formula (50).

Embodiment 107

A process for preparing a compound of formula (48):

comprising:

-   -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45):

-   -   (e) reacting the solution of a compound of formula (45) with        potassium tert-butoxide to produce an intermediate of formula        (46):

-   -   (f) reacting the solution of a compound of formula (46) with a        halogen source to produce an intermediate of formula (47):

wherein X²⁴ is F, Cl, or I;

-   -   (g) reacting the solution of a compound of formula (46) with the        intermediate of formula (47) in the presence of base to form a        compound of formula (48):

-   -   (h) reacting the solution of a compound of formula (48) with        dilute acid to form (49).

Embodiment 108

The process of embodiment 107, wherein the compound of formula (48) is:

Embodiment 109

The process of embodiments 107-108, further comprising any of thefollowing steps:

-   -   (i) treating the compound of formula (49) of step (h) with a        calcium hydroxide or calcium oxide of an alkali or earth        alkaline metal in a suitable solvent;    -   (j) precipitating the compound of formula (50):

-   -   wherein M¹ is Ca or K and x is 1 or 2;    -   in the presence of an organic solvent; or, alternatively,        removing the organic layer by evaporation to afford a crude        crystalline salt of formula (50) as an alcohol solvate or        hydrate;    -   (k) adding one or more anti-solvents to the solid of step (j) in        which the compound of formula (50) is insoluble; and        humidifying the precipitate resultant from step (k) to obtain        crystalline compound of formula (50).

A further aspect is a process for preparing a compound of formula (45):

wherein:

-   -   R²² and R²³ are each independently alkyl, cycloalkyl,        cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,        arylalkyl, heteroaryl, or heteroarylalkyl; and    -   m is 0-4;        comprising:    -   (a) reacting a solution of a cyclic lactone of formula (41):

with a deprotonating reagent to produce an intermediate of formula(41a):

wherein M²² is Li or Zn;

-   -   (b) reacting the intermediate of formula (41a) with a solution        of an alkylhalide of formula (42):

R²²—X²²   42

wherein X²² is halo;

to produce a compound of formula (43):

-   -   (c) reacting the solution of a compound of formula (43) with a        deprotonating reagent to produce an intermediate of formula        (43a):

wherein M²³ is Li or Zn;

-   -   (d) reacting the intermediate of formula (43a) with a solution        of an alkylhalide of formula (44):

R²³—X²³   44

wherein X²³ is halo;

to produce a compound of formula (45).

In some embodiments, m is 1.

In some embodiments, R²² and R²³ are the same. In other embodiments, R²³and R²² are different.

General Synthesis of α,ω-Dicarboxylic Acid-Terminated Dialkane Ethers

Four different methodologies are presented for preparingα,ω-dicarboxylic acid-terminated dialkane ethers: (1) the Reformatskyreaction; (2) acid catalyzed ether synthesis; (3) alkylation; and (4)Williamson ether synthesis.

(1) The Reformatsky Reaction:

Compounds of formula (III) and corresponding salts may be prepared undercertain conditions using a Reformatsky reaction according to Scheme 4.Ethyl 2-bromoisobutyrate XV and halo-butyl ethers II under variousconditions including solvents such as THF, methyl t-butyl ether or andethyl ether, and zinc such as zinc powder with catalytic amount ofiodine or chlorotrimethylsilane, or highly active Rieke® zinc, and attemperatures between 0° C. to 70° C. or in refluxing solvent. Suchprocedures are described in Cui, H.; et al.; Org. & Biomed. Chem. 2013,10(14), 2862-2869 and Gaudemar-Bardone, F.; et al.; Synthesis, 1987, 12,1130-1133.

(2) Acid-Catalyzed Ether Synthesis

Compounds of formula (III) and corresponding acids and salts may beprepared using an acid-catalyzed ether synthesis reaction according toScheme 5. For instance, esters of type 53 can be synthesized bydimerization of alcohols of type 52, using the by the reaction pathwaydescribed in Scheme 7, where alcohols 52 are prepared by methods knownin the art (e.g., for n=3 in two steps by alkylation of benzyl protected4-bromobutanol (commercially available from Sigma-Aldrich) with an alkylisobutyrate (commercially available from various suppliers, such asSigma-Aldrich), and subsequent hydrogenation.

(3) Alkylation Method:

Compounds of formula (III) and corresponding salts may be prepared usingan alkylation method according to Scheme 6. The results of thealkylation studies are presented in Table 1, using the general synthesisdescribed in Scheme 6.

TABLE 1 Alkylation results for gemcabene diethyl ester and analogs. R²R³ X base n m Yield (%) Me Me Cl LDA 1 1  0 Me Me Br LiHMDS 1 1  0 Me MeBr LDA 1 1  24* Me Me I LDA (n-BuLi) 1 1 98 Me Me Br LDA 0 1 85 Me Me ILDA (n-HexylLi) 1 1 91 Me p-Tolyl I LDA 1 1 89 Me Me Br LDA 2 1 79 Me MeBr LDA 2 2 89 *The bromide contained some chloride that lowered theyield

Using n-hexyllithium or n-butyllithium to generate the LDA producedcomparable results. The use of n-hexyllithium is known to be safe andenvironmentally friendly, therefore such a methodology is largelyscalable at multikilogram batches. LiHMDS failed to generate anyproduct. Finally, using larger groups (p-tolyl) on the ester did nothinder the alkylation reaction.

(4) Williamson Ether Synthesis:

Compounds of formula (III) and corresponding salts may be prepared usinga Williamson ether synthesis according to Scheme 7. The results forvarious compounds using the Williamson Ether Synthesis method are listedin Table 2, using the general synthesis described in Scheme 7.

TABLE 2 Williamson Ether Synthesis Results R²¹ R²² R²³ m n X²⁴ Yield (%)Et Methyl Methyl 1 1 Br 0 Et Methyl Methyl 1 1 I trace t-butyl MethylMethyl 1 1 Br 34% t-butyl Methyl Methyl 1 1 I 40%

During the Williamson ether synthesis, the ethyl esters producedprimarily trans-esterification products. Replacing the ethyl ester witht-butyl ester prevented the trans-esterification from occurring. Arepresentative method starting from inexpensive and safe startingmaterials is outlined in Scheme 7a.

The preparation of alcohol 46 begins with, for example, the alkylationof 6-caprolactone using LDA and iodomethane, followed by ring openingwith potassium t-butoxide. Other alkylation methodologies for6-caprolactone may be used, such as ring opening with t-butoxide. Theiodide or the bromide of formula (47) may be directly prepared from thealcohol and coupled by the Williamson ether synthesis methodology.

Exemplary compounds and intermediates that may be prepared by thesemethods are included in Table 3.

TABLE 3 List of Compounds # Structure Name 1

4-Iodobutyl ether 2

6-(5-Ethoxycarbonyl-5- methyl-hexyloxy)-2,2- dimethylhexanoic acid ethylester 3

6-(5-Carboxyl-5-methyl- hexyloxy)-2,2- dimethylhexanoic acid 4

Gemcabene 5

4-Bromobutyl ether 6

6-Benzyloxy-2,2- dimethylhexanoic acid ethyl 6-Benzyloxy-2,2- ester 7

6-Hydroxy-2,2- dimethylhexanoic acid ethyl ester 8

6-Bromo-2,2- dimethylhexanoic acid ethyl ester 9

6-Benzyloxy-2,2- dimethylhexanoic acid 11

6-Benzyloxy-2,2- dimethylhexanoic acid tert- butyl ester 12

6-Hydroxy-2,2- dimethylhexanoic acid t-butyl ester 13

6-Bromo-2,2- dimethylhexanoic acid tert- butyl ester 14

6-(5-tert-Butoxycarbonyl-5- methyl-hexyloxy)-2,2- dimethyl-hexanoic acidtert- butyl ester (14, gemcabene di-t-butyl ester) 15

6-Iodo-2,2-dimethylhexanoic acid t-butyl ester 16

Ethyl 2-p-tolylpropionate 17

Diethyl 6,6′-oxybis(2- methyl-2-(p-tolyl)hexanoate) 18

6,6′-Oxybis(2-methyl-2-(p- tolyl)hexanoic acid) 19

7-(6-Ethoxy-carbonyl-6- methylheptyloxy)-2,2- dimethylheptanoic acidethyl ester 20

7-(5-Ethoxy-carbonyl-5- methylhexyloxy)-2,2- dimethyl-heptanoic acidethyl ester 21

6-(4-Ethoxy-carbonyl-4- methylpentyloxy)-2,2- dimethyl-hexanoic acidethyl ester 22

3-(Tetrahydro-pyran-2- yloxy)-propan-1-ol 23

2-[3-(4-Bromobutoxy)- propoxy]-tetrahydropyran 24

3-(4-Bromobutoxy)-propan- 1-ol 25

1-Bromo-4-(3- bromopropoxy)-butane 26

3,3-Dimethyl-oxepan-2-one 27

5-(Tetrahydro-pyran-2- yloxy)-pentan-1-ol 28

2-[5-(5-Bromopentyloxy)- pentyloxy]-tetrahydropyran 29

5-(5-Bromopentyloxy)- pentan-1-ol 30

1-Bromo-5-(5- bromopentyloxy)-pentane 31

2-[5-(4-Bromobutoxy)- pentyloxy]-tetrahydropyran 32

5-(4-Bromobutoxy)-pentan-1- ol 33

1-Bromo-5-(4-bromobutoxy)- pentane

General Synthesis of Gemcabene

Alkylation Approach:

A representative synthesis of gemcabene is shown in Scheme 8. In thisrepresentative example, 4-Chlorobutyl ether was converted into4-iodobutyl ether 1 with NaI in acetone in 95% yield. The alkyl iodidewas treated with ethyl isobutyrate in the presence of LDA, which isfreshly prepared from diisopropylamine/n-hexyl lithium or n-butyllithium, to provide the diester 2 in a high yield. Alternate examples inwhich the LDA was prepared using either butyllithium or hexyllithiumproduced comparable yields. The diester 2 was saponified to provide thediacid 3, followed by transformation into gemcabene calcium 4.

Unexpectedly, experiments using 4-chloro- and 4-bromobutyl ethers didnot undergo α-alkylation of ethyl isobutyrate to produce diester 2. Noevidence of a coupling product was found using 4-chlorobutyl ether as astarting material (Scheme 9).

The use of 4-bromobutyl ether as a starting material resulted in theformation of diester 2, but with different reaction kinetics (Scheme10).

Reformatsky Approach:

Gemcabene may be prepared using a Reformatsky coupling reaction betweenethyl 2-bromoisobutyrate and 4-chalobutyl ethers (Scheme 11) undervarious conditions. These conditions include various solvents (such asTHF, methyl-t-butyl ether, and ethyl ether), various types of zinc (zincpowder with catalytic amounts of iodine or chlorotrimethylsilane orhighly active Rieke® zinc), and various reaction temperatures between 0°C. to 70° C.

Acid-Catalyzed Ether Synthesis:

Gemcabene may be synthesized by dimerization of alcohols, such asalcohol 7 below, using the by the reaction pathway described in Scheme12. Alcohol 7 was prepared in two steps by alkylation of benzylprotected 4-bromobutanol with an alkyl isobutyrate, followed byhydrogenation.

Dimerization of alcohol 7 in the presence of various acid catalysts,such as sulfuric acid or nalfion NR50 (acidic resin), in organicsolvents, such as ethers or hydrocarbons, may produce gemcabene. Thisprocess may result in a complex mixture of products formed due totrans-esterification (Scheme 13).

Williamson Ether Synthesis:

Another representative example of a process for preparing gemcabene isshown in the Willaimson ether synthesis in Scheme 14. Alcohol 7 wastreated with sodium hydride in the presence of corresponding bromide 8.Bromide 8 was prepared by alkylating 1,4-dibromobutane with ethylisobutyrate.

If trans-esterification occurs instead of the expected displacementreaction, the bromide 8 may be converted to the iodide before proceedingwith the reaction.

To reduce the trans-esterification products and produce higher yield ofthe desired products, the ethyl esters may be replaced withsterically-hindered esters, such as, but not limited to, t-butyl esters.A representative example of this process is shown in Scheme 15. In thisexample, hydrolysis of intermediate 6 to form acid 9, followed byt-butylation in the presence of, for example, isourea 10, produces thet-butyl ester. The protected t-butyl ester 11 can be hydrogenated toafford alcohol 12 (Scheme 15) in quantitative yield.

The corresponding bromide 13 may be prepared by alkylation of1,4-dibromobutane with t-butyl isobutyrate. The t-butyl isobutyrate maybe prepared by trans-esterification of methyl isobutyrate using sodiumtert-butoxide in 51% yield according to the literature procedure (Scheme16).

Alcohol 12 was reacted in with bromide 13 in the presence of hydratingagents, such as, but not limited to sodium hydride, in aprotic dipolarsolvents, such as, but not limited to, DMF. In this representativeexample, gemcabene di-t-butyl ester was obtained by reacting bromide 13with alcohol 12 in the presence of sodium hydride and DMF at 5° C.,followed by warming to room temperature and stirring for 20 hours(Scheme 17).

Unexpectedly, there was no indication of the trans-esterificationproducts. Some unreacted alcohol 12 and bromide 13 were present in thecrude NMR, along with some elimination product from the bromide.However, yields and conversions improved with longer reaction times andwhen using more than 1 equivalent of sodium hydride and bromide.

Bromide 13 was converted to the iodide by refluxing with sodium iodidein acetone. Further, iodide 15 was reacted with alcohol 12, as describedin Scheme 18.

The experiment produced slightly higher yield than the bromide. Onceagain, no trans-esterification side products were present in the crudematerial. The elimination byproduct was present in higher amounts. Theremainder was unreacted alcohol 12 and a trace of the iodide 15. Thegemcabene t-butyl diester was converted to gemcabene diacid 3 with 10%TFA in dichloromethane.

Alkylation Method: Other α,ω-Dicarboxylic Acid-Terminated DialkaneEthers Synthesis of 6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoic acid)

As shown in Scheme 19, the alkylation process of Scheme 8 in alkylationmethod may be used to produce other α,ω-dicarboxylic acid-terminateddialkane ethers, such as 6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoic acid)18. Ethyl p-tolylacetate was α-methylated with iodomethane in thepresence of LDA to give the ester 16, followed by α-alkylation with4-iodobutyl ether with LDA to give the diester 17. The dicarboxylic acid18 was obtained by saponification of 7 with aqueous KOH in ethanol.

Synthesis of the 5-5, 5-4, 4-3 Analogs of Gemcabene Diethyl Ester

Three analogs of gemcabene diethyl ester (compounds 19, 20, 21 in Scheme20) were prepared by the alkylation method using the appropriatedibromide compounds.

Each analog was prepared in the same fashion, altering only thedibromide compounds. A representative procedure for preparing compound21 is shown in Scheme 17.

In the representative example for producing analong 21, propane diol wasprotected with a THP group to prepare protected alcohol 22. Theprotected alcohol was reacted with 1,4-dibromobutane in the presence ofsodium hydride to prepare bromide 23 after reflux for 20 hours in THF. Asignificant amount of unreacted alcohol 22 was recovered. Running thereaction in DMF may result in an increased yield. The THP group presentin bromide 23 was removed by stirring in methanol with p-toluenesulfonicacid to prepare alcohol 24. The alcohol was converted to the bromide bytreatment with carbon tetrabromide and triphenylphosphine to generatethe dibromide 25 in 91% yield. Once the dibromide was prepared, thealkylation with ethyl isobutyrate was conducted in the same fashion aswith gemcabene in Scheme 4. Ethyl isobutyrate was deprotonated with LDAat −78° C. followed by the addition of dibromide 26, and the reactionwas subsequently warmed to room temperature to provide diester 21. Theprocedures were repeated for compounds 19 and 20. In the case ofcompound 19, the alkylation with dibromide 26 (Scheme 22) provideddiester 19.

A comparable but slightly lower yield was seen in the alkylation withethyl isobutyrate to prepare analog 20. For each analog, the alkylationproduced the desired analogs in favorable yields.

SYNTHETIC EXAMPLES Example 1

Gemcabene calcium prepared from ethyl isobutyrate according to Scheme23.

In the first step of the reaction, ethyl isobutyrate is deprotonated inthe presence of a suitable non-pyrophoric lithium derivative, such asn-hexyllithium, n-heptyllithium, and n octyllithium. The reaction isperformed by either the addition of the halo-ester of formula (6) to thelithiation agent in a suitable solvent, or, conversely, by addition ofthe lithiation agent to the halo-ester solution in a suitable solvent.To an ethyl isobutyrate solution in a suitable organic solvent is addedunder stirring approximately 1 to approximately 2.2 eq of the lithiumderivative at approximately 2.5 M concentration under an inertatmosphere such as nitrogen or argo gas at a rate of approximately 1.5moles per hour. The solution is maintained at a constant temperaturewithin the range of approximately −78° C. to approximately −10° C.Optionally, the base is diluted in a suitable organic solvent beforeaddition. Suitable organic solvents include, but are not limited to,dichloromethane, diethyl ether, tetrahydrofuran, 2-methytetrahydrofuran,dimethylformamide, dimethyl sulfoxide, benzene, toluene, xylene,hydrocarbon solvents (such as pentane, hexane, and heptane), andmixtures thereof. After addition of the base, the reaction mixture isallowed to stir for approximately 1 hr to approximately 12 hr. Thenbis(halobutyl)ether, dissolved in a suitable solvent, is added,preferably at a rate such that the reaction-mixture temperature remainswithin approximately one to five degrees of the initial reaction-mixturetemperature. A suitable bis(halobutyl)ether is a bis(chloro),bis(bromo), or a bis(iodo) ether. These compounds are commerciallyavailable, for example, from FCH Group Reagents for Synthesis, or can beprepared as described, for instance, in Mueller R. et al., J. Med. Chem.2004, 47, 5183-5197. After completion of the addition, thereaction-mixture temperature can be adjusted to within a temperaturerange of approximately −20° C. to approximately RT, preferably toapproximately RT. The reaction mixture is allowed to stir until thereaction is substantially complete, as determined using an appropriatedanalytical method, such as thin-layer chromatography or high-performanceliquid chromatography. Then, the reaction mixture is quenched, and thediester compound of formula (7) is isolated by workup. Gemcabene is thensynthesized by reacting the diester of formula (7) with a metal salt,base, or oxide according to the protocol described above for theformation of the α,ω-dicarboxylic acid-terminated dialkane ether salt offormula (IV).

Example 2

Gemcabene prepared from ethyl α-bromoisobutyrate of formula (10)according to Scheme 24.

In a typical procedure, ethyl α-bromoisobutyrate of formula (10) istreated at 0° C. with 1 eq of powdered zinc under an inert atmosphere,such as nitrogen or argon gas. The mixture is stirred at approximately0° C. to approximately 10° C. until nearly all the zinc has reacted(approximately 3 hr). Alternatively, iodine is added to initiate thereaction. Bis(halobutyl)ether of formula (6) (0.5 eq), is added dropwiseto the flask over 1 hr, and the mixture is allowed to warm to 25° C.over several hours, after which time the mixture is heated at 50° C. for1 hr and cooled. Aqueous ammonium chloride is added to the mixture, andthe aqueous layer is extracted with an organic solvent, dried over adrying agent, and evaporated to give the crude product.

Example 3: Diethyl 7,7′-oxybis(2,2-dimethylheptanoate)

Diethyl 7,7′-oxybis(2,2-dimethylheptanoate) may be prepared according tothe processes of Examples 1 or 2 above, wherein the α,ω-halo-terminateddialkane ether of formula (2) is bis(halopentyl)ether.

Example 4: Ethyl7-((6-ethoxy-5,5-dimethyl-6-oxohexyl)oxy)-2,2-dimethylheptanoate

Ethyl 7-((6-ethoxy-5,5-dimethyl-6-oxohexyl)oxy)-2,2-dimethylheptanoatemay be prepared according to the processes of Examples 1 or 2 above,wherein the α,ω-halo-terminated dialkane ether of formula (2) is1-chloro-5-(4-chlorobutoxy)pentane.

Example 5: Ethyl6-((5-ethoxy-4,4-dimethyl-5-oxopentyl)oxy)-2,2-dimethylhexanoate

Ethyl 6-((5-ethoxy-4,4-dimethyl-5-oxopentyl)oxy)-2,2-dimethylhexanoatemay be prepared according to the processes of Examples 1 or 2 above,wherein the α,ω-halo-terminated dialkane ether of formula (2) is1-halo-4-(3-chloropropoxy)butane.

Example 6: Diethyl 6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoate

Diethyl 6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoate) may be preparedaccording to the process of Example 1, above, wherein the compound offormula (I) is ethyl 2-o-tolyl-propionate. Diethyl 6,6′-oxybis(2-methyl2-o-tolyl-hexanoate) may also be prepared according to the process ofExample 2, above, wherein the compound of formula (9) is ethyl2-bromo-2-o-tolyl-propionate.

Example 7: 4-Iodobutyl Ether (1)

Acetone (previously dried over 4 Å molecular sieve, 200 mL) was added toa stirred mixture of 4-chlorobutyl ether (10.0 g, 50.2 mmol) and sodiumiodide (24.9 g, 166 mmol, 3.3 eq.), and the mixture was heated at refluxfor 48 h. The reaction mixture was cooled to room temperature and thenfiltered. The inorganic solid was rinsed with acetone (100 mL), and thefiltrate was concentrated under reduced pressure. The residue was takenup in MTBE (200 mL). The resulting mixture was washed with water (200mL), 2% sodium thiosulfate (200 mL), and brine (200 mL) sequentially andthen concentrated under reduced pressure. The crude product was purifiedthrough a silica-gel flash chromatography eluted with heptane/ethylacetate (40:1) to give the desired product (18.3 g, 95% yield) as ayellow oil: ¹H NMR (300 MHz, CDCl₃) δ 3.43 (t, 4H, J=6.3 Hz), 3.22 (t,4H, J=6.9 Hz), 1.91 (m, 4H), 1.67 (m, 4H).

Example 8: 6-(5-Ethoxycarbonyl-5-methyl-hexyloxy)-2,2-dimethyl-hexanoicacid ethyl ester (2)

To a stirred solution of diisopropylamine (1.19 g, 11.8 mmol) inanhydrous THF (20 mL) cooled in a dry ice bath was added hexyllithium(2.3 M, 5.1 mL, 11.8 mmol), and the mixture was stirred for 40 minutes.Ethyl isobutyrate (1.37 g, 11.8 mmol) was added drop-wise, and 30minutes later 4-iodobutyl ether (1.63 g, 4.27 mmol) was added. Afteraddition, the reaction mixture was slowly warmed to room temperature andstirred overnight. The reaction mixture was poured into cold 1 NHClsolution (50 mL) and then extracted with MTBE (3×30 mL). The combinedextracts were washed with 2% sodium thiosulfate (50 mL) and brine (30mL), dried over sodium sulfate, and concentrated under reduced pressure.The residue was purified through a silica-gel flash chromatographyeluted with a gradient of heptane/ethyl acetate (40:1 to 10:1) to givethe desired diester (1.40 g, 91% yield) as a colorless oil: ¹H NMR (300MHz, CDCl₃) δ 4.11 (q, 4H, J=7.2 Hz), 3.37 (t, 4H, J=6.6 Hz), 1.52 (m,8H), 1.29 (m, 4H), 1.24 (t, 6H, J=7.2 Hz), 1.16 (s, 12H); ¹³C NMR (75MHz, CDCl₃) δ 177.98, 70.68, 60.13, 42.11, 40.48, 30.17, 25.05, 21.59,14.21.

Example 9: 6-(5-Carboxyl-5-methyl-hexyloxy)-2,2-dimethyl-hexanoic acid(3)

To a stirred solution of6-(5-ethoxycarbonyl-5-methyl-hexyloxy)-2,2-dimethyl-hexanoic acid ethylester (2.68 g, 7.48 mmol) in absolute ethanol (50 mL) was added aqueousKOH (2.2 M, 34 mL, 74.8 mmol), and the mixture was stirred at 55° C. for24 h. The reaction mixture was cooled to room temperature and thenconcentrated under reduced pressure to remove ethanol. The remainingmixture was extracted with MTBE (50 mL), and the extract was discarded.The aqueous layer was acidified with 3 NHCl (30 mL) slowly. Theresulting mixture was extracted with MTBE (3×30 mL). The combinedextracts were dried over sodium sulfate and concentrated under reducedpressure. The residue was purified through a silica-gel flashchromatography eluted with heptane/ethyl acetate (from 4:1 to 2:1) togive the desired diacid (1.53 g, 84% yield) as a white solid: ¹H NMR(300 MHz, CDCl₃) δ 3.37 (t, 4H, J=5.1 Hz), 1.49 (m, 8H), 1.35 (m, 4H),1.19 (s, 12H).

Alternate Synthesis from the Di-Tert-Butyl Ester:

The di-tert-butyl ester of gemcabene (0.25 g, 0.36 mmol) was dissolvedin dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL). The mixturewas stirred at room temperature for 20 hours. After 20 hours, thesolution was concentrated and dried to a constant weight under highvacuum. The experiment produced the desired diacid (105 mg, 97% yield)as a colorless solid: ¹H NMR (300 MHz, CDCl₃) δ 11.23 (s, 2H), 3.37 (t,4H, J=5.1 Hz), 1.49 (m, 8H), 1.35 (m, 4H), 1.19 (s, 12H).

Example 10: Gemcabene Calcium (4)

To a stirred solution of6-(5-carboxyl-5-methyl-hexyloxy)-2,2-dimethyl-hexanoic acid (1.34 g,4.43 mmol) in absolute ethanol (30 mL) was added CaO (0.25 g, 4.43mmol), and the mixture was stirred at reflux for two days. The reactionmixture was cooled to room temperature, diluted with MTBE (30 mL), andthen stirred for two hours. The mixture was settled for 30 minutes andthen filtered. The crop (4.32 g) was dried at 80° C. for 24 h under highvacuum to give a white solid (1.29 g). To the solid was added DIUF water(0.26 g, 14.4 mmol), and the mixture was stirred at 100° C. for fivehours and then dried under high vacuum at 95° C. for 1 h and then atroom temperature overnight to give the desired product (1.24 g, 82%yield, 99.9% HPLC purity) as a white solid: ¹H NMR (300 MHz, D₂O-TSP) δ3.51 (t, 4H, J=6.9 Hz), 1.55 (m, 4H), 1.46 (m, 4H), 1.26 (m, 4H), 1.07(s, 12H); ¹³C NMR (75 MHz, D₂O-1,4-dioxane) δ 188.05, 70.51, 43.36,40.71, 29.25, 25.43, 21.27.

Example 11: 4-Bromobutyl Ether (5)

A sealed tube was charged with a magnetic stirring bar, lithium bromide(2.21 g, 25.5 mmol), tetrbutylammonium bromide (0.82 g, 2.55 mmol, 0.1eq.), water (0.022 g, 1.22 mmol) and 4-chlorobutyl ether (1.99 g, 10.0mmol). The mixture was stirred at 95° C. for 48 h. The mixture wasdiluted with heptane (30 ml) and water (20 mL), and the layers wereseparated. The organic layer was washed with brine (20 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure. Theresidue was purified through a silica-gel chromatography eluted withheptane/ethyl acetate (40:1) to give 4-bromobutyl ether (1.29 g, 45%yield, containing ˜30% 4-bromobutyl 4-chlorobutyl ether) as a colorlessoil: ¹H NMR (300 MHz, CDCl₃) δ 3.44 (t, 8H, J=6.0 Hz), 1.97 (m, 4H),1.71 (m, 4H).

Example 12: 6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester (6)

Ethyl isobutyrate (4.0 g, 34.4 mmol) was dissolved in dry THF (50 mL)under argon. The flask was cooled in a dry ice/acetone bath, and 2M LDA(21 ml, 42 mmol) was added drop-wise over 5-10 minutes. The solutionstirred for 30 minutes, and benzyl 4-bromobutyl ether (8.0 g, 32.9 mmol)was added. The solution slowly warmed to room temperature and stirredovernight. After 18 hours at room temperature, water (50 ml) was addedalong with ethyl acetate (50 mL). The layers were separated, and theethyl acetate layer was extracted with 5% hydrochloric acid solution (50ml), followed by brine (50 mL). The ethyl acetate extract was dried oversodium sulfate, filtered, and concentrated. The remaining oil waspurified on silica gel (200 g), eluting with 1:20 ethylacetate/heptanes. The experiment generated 8.6 g (95% yield) of6-benzyloxy-2,2-dimethylhexanoic acid ethyl ester as a clear oil. ¹H NMR(300 MHz, CDCl₃) δ 7.40-7.25 (m, 5H), 4.51 (s, 2H), 4.12 (q, 2H, J=7.2Hz), 3.48 (t, 2H, J=6.6 Hz), 1.64-1.53 (m, 4H), 1.39-1.32 (m, 5H), 1.17(s, 6H).

Example 13: 6-Hydroxy-2,2-dimethylhexanoic acid ethyl ester (7)

6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester (9.6 g, 34.7 mmol) wasdissolved in ethyl acetate (100 mL) and added to 20% palladium on carbon(0.8 g). The mixture was hydrogenated at 40 psi hydrogen in a Parrapparatus for 24 h. The mixture was then purged with nitrogen andfiltered through a pad of celite and concentrated. The experimentproduced 6-hydroxy-2,2-dimethyl-hexanoic acid ethyl ester (5.8 g, 88%yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 4.10 (q, 2H, J=7.2 Hz),3.57 (t, 2H, J=5.4 Hz), 1.51-1.45 (m, 4H), 1.33-1.23 (m, 5H), 1.13 (s,6H).

Example 14: 6-Bromo-2,2-dimethylhexanoic acid ethyl ester (8)

Ethyl isobutyrate (10.0 g, 86.0 mmol) was dissolved in dry THF (100 mL)under argon. The flask was cooled in a dry ice/acetone bath, and 2M LDA(51.8 ml, 103.6 mmol) was added drop-wise over 5-10 minutes. Thesolution stirred for 30 minutes, and 1,4-dibromobutane (22.3 g, 103mmol) was added. The solution slowly warmed to room temperature andstirred overnight. After 18 h at room temperature, water (100 ml) wasadded along with ethyl acetate (100 mL). The layers were separated, andthe ethyl acetate layer was extracted with 5% hydrochloric acid solution(100 ml) followed by brine (100 mL). The ethyl acetate extract was driedover sodium sulfate, filtered, and concentrated. The remaining oil waspurified twice on silica gel (200 g), eluting with 1:10 ethylacetate/heptane. The experiment generated 12.2 g (56% yield) of6-bromo-2,2-dimethylhexanoic acid ethyl ester as a clear oil. ¹H NMR(300 MHz, CDCl₃) δ 4.14 (q, 2H, J=7.2 Hz), 3.52 (t, 2H, J=56.9 Hz),1.88-1.82 (m, 2H), 1.58-1.36 (m, 2H), 1.36 (t, 3H, J=7.2 Hz), 1.18 (s,6H).

Example 15: 6-Benzyloxy-2,2-dimethylhexanoic acid (9)

6-Benzyloxy-2,2-dimethylhexanoic acid ethyl ester (7.40 g, 26.6 mmol)was dissolved in ethanol (120 mL) with potassium hydroxide (7.40 g, 132mmol) and water (40 mL). The solution was heated to 50-60° C. overnight.After 18 h, the solution was cooled to room temperature and concentratedto remove ethanol. Water (150 mL) was added, and the solution wasextracted with heptanes (100 mL). The layers were separated and theaqueous layer was acidified to pH=2 with concentrated hydrochloric acid.The product was extracted twice with ethyl acetate (50 mL). The combinedethyl acetate extracts were washed with brine (50 mL), dried over sodiumsulfate, filtered, and concentrated. The experiment produced 4.72 g (72%yield) of 6-benzyloxy-2,2-dimethylhexanoic acid as a white solid. ¹H NMR(300 MHz, CDCl₃) δ 7.35-7.25 (m, 5H), 4.50 (s, 2H), 3.48 (t, 2H, J=6.6Hz), 1.64-1.53 (m, 4H), 1.40-1.37 (m, 2H), 1.19 (s, 6H).

Example 16: 6-Benzyloxy-2,2-dimethylhexanoic acid tert-butyl ester (11)

6-benzyloxy-2,2-dimethylhexanoic acid (2.50 g, 9.98 mmol) was dissolvedin dichloromethane (50 mL) with t-butyl-dicyclohexyl isourea (4.50 g,16.05 mmol). The mixture stirred for 72 h at room temperature underargon. After 72 h, the mixture was filtered to remove DCU. The filtratewas washed with saturated sodium bicarbonate solution (50 mL). Thedichloromethane was dried over sodium sulfate, filtered, andconcentrated. The remaining oil was filtered through silica gel (30 g)with 10% ethyl acetate/heptanes. The experiment generated 2.20 g (72%yield of 6-Benzyloxy-2,2-dimethylhexanoic acid tert-butyl ester as aclear oil. ¹H NMR (300 MHz, CDCl₃) δ 7.35-7.25 (m, 5H), 4.50 (s, 2H),3.48 (t, 2H, J=6.3 Hz), 1.62-1.49 (m, 4H), 1.42 (s, 9H), 1.40-1.37 (m,2H), 1.11 (s, 6H).

Example 17: 6-Hydroxy-2,2-dimethylhexanoic acid t-butyl ester (12)

6-Benzyloxy-2,2-dimethylhexanoic acid tert-butyl ester (2.20 g, 7.18mmol) was dissolved in ethyl acetate (40 mL) and added to 10% palladiumon carbon (1.35 g). The mixture was hydrogenated at 40 psi hydrogen in aParr apparatus for 48 h. The mixture was then purged with nitrogen andfiltered through a pad of celite and concentrated. The experimentproduced 6-hydroxy-2,2-dimethyl-hexanoic acid t-butyl ester (1.60 g,100% yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 3.65 (t, 2H, J=6.6Hz), 1.58-1.50 (m, 4H), 1.43 (s, 9H), 1.39-1.30 (m, 2H), 1.12 (s, 6H).

Example 18: 6-Bromo-2,2-dimethylhexanoic acid tert-butyl ester (13)

t-Butyl isobutyrate (1.90 g, 13.1 mmol) was dissolved in dry THF (40 mL)under argon. The flask was cooled in a dry ice/acetone bath, and 2M LDA(7.2 mL, 14.4 mmol) was added drop-wise over 5-10 minutes. The solutionstirred for 30 minutes, and 1,4-dibromobutane (8.0 g, 37 mmol) wasadded. The solution slowly warmed to room temperature and stirredovernight. After 18 h at room temperature, water (50 ml) was added alongwith ethyl acetate (50 mL). The layers were separated, and the ethylacetate layer was extracted with 5% hydrochloric acid solution (50 ml)followed by brine (50 mL). The ethyl acetate extract was dried oversodium sulfate, filtered, and concentrated. The remaining oil waspurified twice on silica gel (30 g), eluting with 1:20 ethylacetate/heptane. The experiment generated 1.0 g (28% yield) of6-bromo-2,2-dimethylhexanoic acid t-butyl ester as a clear oil. ¹H NMR(300 MHz, CDCl₃) δ 3.42 (t, 2H, J=6.9 Hz), 1.88-1.83 (m, 2H), 1.58-1.36(m, 2H), 1.47 (s, 9H), 1.14 (s, 6H).

Example 19:6-(5-tert-Butoxycarbonyl-5-methylhexyloxy)-2,2-dimethyl-hexanoic acidtert-butyl ester (14)

Sodium hydride (60%, 50 mg, 1.25 mmol) was mixed with DMF (5 mL) underargon. The flask was cooled in a water/ice batch, and6-hydroxy-2,2-dimethylhexanoic acid t-butyl ester (0.26 g, 1.20 mmol)was added. The mixture was stirred for 10-20 minutes at 5° C. when6-bromo-2,2-dimethylhexanoic acid t-butyl ester (0.35 g, 1.25 mmol) inDMF (1.0 mL) was added. The mixture was slowly warmed to roomtemperature and stirred overnight under argon. After 20 h at roomtemperature, water (20 mL) was added, and the product was extracted withdiethyl ether (2×20 mL). The combined ether extracts were washed withwater (20 mL), dried over sodium sulfate, filtered, and concentrated.The remaining oil was purified on silica gel eluting with 10% ethylacetate/heptanes. The experiment produced the d-t-butyl ester ofgemcabene (0.17 g, 34% yield) as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ3.38 (t, 4H, J=6.9 Hz), 1.55-1.45 (m, 8H), 1.43 (s, 18H), 1.35-1.25 (m,4H), 1.11 (s, 12H).

Alternate Procedure:

Sodium hydride (60%, 50 mg, 1.25 mmol) was mixed with DMF (5 mL) underargon. The flask was cooled in a water/ice batch, and6-hydroxy-2,2-dimethylhexanoic acid t-butyl ester (0.26 g, 1.20 mmol)was added. The mixture was stirred for 30-40 minutes at 5° C. when6-iodo-2,2-dimethylhexanoic acid t-butyl ester (0.50 g, 1.53 mmol) wasadded. The mixture was slowly warmed to room temperature and stirredovernight under argon. After 20 h at room temperature, water (20 mL) wasadded, and the product was extracted with diethyl ether (2×20 mL). Thecombined ether extracts were washed with water (20 mL), dried oversodium sulfate, filtered, and concentrated. The remaining oil waspurified on silica gel eluting with 10% ethyl acetate/heptanes. Theexperiment produced the d-t-butyl ester of gemcabene (0.20 g, 40% yield)as a clear oil. ¹H NMR (300 MHz, CDCl₃) δ 3.38 (t, 4H, J=6.9 Hz),1.55-1.45 (m, 8H), 1.43 (s, 18H), 1.35-1.25 (m, 4H), 1.11 (s, 12H). HRMS(ESI): [M+NH₄]⁺=432.3684; found 432.3696.

Example 20: 6-Iodo-2,2-dimethylhexanoic acid t-butyl ester (15)

6-Bromo-2,2-dimethylhexanoic acid tert-butyl ester (0.66 g, 2.36 mmol)was dissolved in acetone (30 mL) with sodium iodide (0.90 g, 6.0 mmol).The mixture was heated to reflux for 2 h under argon. The mixture wascooled to room temperature, filtered, and concentrated. Heptane (30 mL)was added along with water (30 mL). The layers were separated, and theheptanes was dried over sodium sulfate, filtered, and concentrated. Theexperiment produced 6-iodo-2,2-dimethylhexanoic acid t-butyl ester (0.71g, 92% yield) as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 3.19 (t, 2H,J=6.6 Hz), 1.86-1.76 (m, 2H), 1.51-1.34 (m, 2H), 1.45 (s, 9H), 1.13 (s,6H).

Example 21: Ethyl 2-p-tolylpropionate (16)

To a stirred solution of ethyl p-tolylacetate (1.78 g, 10.0 mmol) inanhydrous THF (15 mL) cooled in a dry ice bath was added lithiumdiisopropylamide (2 M, 5.0 mL, 10 mmol) drop-wise. After the mixture wasstirred for 30 minutes, iodomethane (1.42 g, 10.0 mmol) was addeddrop-wise. After addition, the reaction mixture continued to be stirredat −78° C. for 30 minutes and then at room temperature overnight. Thereaction was quenched with cold 1 NHCl solution (20 mL), and theresulting mixture was extracted with MTBE (2×30 mL). The combinedextracts were washed with 2% sodium thiosulfate (50 mL), brine (30 mL),dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified through a silica-gel flashchromatography eluted with heptane/ethyl acetate (60:1) to give thedesired product (1.37 g, 71% yield) as a light yellow oil: ¹H NMR (300MHz, CDCl₃) δ 7.19 (d, 2H, J=7.8 Hz), 7.13 (d, 2H, J=7.8 Hz), 4.11 (m,2H), 3.67 (q, 1H, J=7.2 Hz), 2.33 (s, 3H), 1.47 (d, 3H, J=7.2 Hz), 1.20(t, 3H, J=7.2 Hz).

Example 22: Diethyl 6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoate) (17)

To a stirred solution of diisopropylamine (0.68 g, 6.8 mmol) inanhydrous THF (15 mL) cooled in a dry ice bath was added hexyllithium(2.3 M, 2.9 mL, 6.8 mmol), and the mixture was stirred for 40 minutes.Ethyl 2-p-tolylpropionate (1.30 g, 6.76 mmol) was added drop-wise; 30minutes later, followed by addition of 4-iodobutyl ether (0.93 g, 2.5mmol). After addition, the reaction mixture was slowly warmed to roomtemperature and stirred for three days. The reaction mixture was pouredinto cold 1 NHCl solution (30 mL) and then extracted with MTBE (3×30mL). The combined extracts were washed with 2% sodium thiosulfate (50mL) and brine (50 mL), dried over sodium sulfate, and concentrated underreduced pressure. The residue was purified through a silica-gel flashchromatography eluted with a gradient of heptane/ethyl acetate (40:1 to10:1) to give the desired diester (1.10 g, 89% yield) as a light yellowoil: ¹H NMR (300 MHz, CDCl₃) δ 7.19 (d, 4H, J=8.4 Hz), 7.11 (d, 4H,J=8.4 Hz), 4.11 (q, 4H, J=7.2 Hz), 3.34 (t, 4H, J=6.6 Hz), 2.32 (s, 6H),2.03 (m, 2H), 1.87 (m, 2H), 1.54 (m, 4H), 1.51 (s, 6H), 1.22 (m, 4H),1.18 (t, 6H, J=7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) δ 176.32, 141.10,136.06, 128.98, 125.82, 70.62, 60.62, 49.80, 39.08, 30.21, 22.70, 21.44,20.90, 14.08.

Example 23: 6,6′-Oxybis(2-methyl-2-(p-tolyl)hexanoic acid) (18)

To a stirred solution of diester diethyl6,6′-oxybis(2-methyl-2-(p-tolyl)hexanoate) (1.07 g, 2.11 mmol) inabsolute ethanol (20 mL) was added aqueous KOH (2.2 M, 9.6 mL, 21 mmol),and the mixture was stirred at 55° C. for 48 h. The reaction mixture wascooled to room temperature and then concentrated under reduced pressureto remove ethanol. The remaining mixture was diluted with water (10 mL)and then acidified with 3 NHCl (10 mL) slowly. The resulting cloudymixture was extracted with MTBE (3×30 mL). The combined extracts weredried over sodium sulfate and concentrated under reduced pressure. Theresidue was purified through a silica-gel flash chromatography elutedwith heptane/ethyl acetate (from 6:1 to 2:1), followed by lyophilizationto give the desired dicarboxylic acid (0.56 g, 64% yield, 98.7% HPLCpurity) as a colorless oil: ¹H NMR (300 MHz, CDCl₃) δ 7.24 (m, 4H), 7.13(m, 4H), 3.50 (m, 1H), 3.40 (m, 2H), 3.32 (m, 1H), 2.33 (s, 3H), 2.31(s, 3H), 2.16 (m, 2H), 1.83 (m, 2H), 1.58 (m, 4H), 1.50 (s, 3H), 1.46(s, 3H), 1.40 (m, 4H); ¹³C NMR (75 MHz, CDCl₃) δ 182.60, 182.39, 141.25,141.04, 136.43, 129.10, 125.92, 125.81, 69.99, 69.96, 50.38, 50.31,38.95, 38.39, 30.25, 30.23, 24.09, 23.71, 22.06, 20.90.

Example 24: 3-(Tetrahydropyran-2-yloxy)-propan-1-ol (22)

1,3-Propanediol (34.2 g, 0.45 mol) and p-toluenesulfonic acidmonohydrate (0.66 g, 3.47 mmol) were dissolved in a mixture of THF (100mL) and dichloromethane (30 mL). The flask was cooled in an ice bath,and 3,4-dihydropyran (12.0 g, 0.14 mol) was added drop-wise over 20-30minutes. After 2 hours of stirring, the ice bath was removed, and thereaction was stirred at room temperature for 2 hours. After 2 hours, thereaction was slowly poured into water (500 mL) that contained potassiumcarbonate (12 g). The product was extracted with ethyl acetate (2×250mL). The combined ethyl acetate extracts were washed with water (2×250mL) and brine (100 mL), dried over sodium sulfate, filtered, andconcentrated. The crude oil was purified by column chromatography onsilica gel (250 g), eluting with 3:1 heptane/ethyl acetate. Theprocedure generated 7.24 g (32% yield) of3-(tetrahydropyran-2-yloxy)-propan-1-ol, as a colorless oil. ¹H NMR (300MHz, CDCl₃) δ 4.59 (t, 1H, J=2.4 Hz), 3.98-3.78 (m, 4H), 3.77-3.50 (m,2H), 2.37 (t, 1H, J=5.7 Hz), 1.90-1.70 (m, 4H), 1.60-1.53 (m, 4H).

Example 25: 2-[3-(4-Bromobutoxy)-propoxy]-tetrahydropyran (23)

3-(Tetrahydropyran-2-yloxy)-propan-1-ol (7.24 g, 45.2 mmol) wasdissolved in dry THF (120 mL) under argon with 60% sodium hydride (3.6g, 54.2 mmol). The mixture was stirred for 30 minutes at roomtemperature. 1,4-dibromobutane (12.0 g, 55.5 mmol) was added and themixture was heated to reflux for 22 h. After 22 h, the solution wascooled to room temperature and poured into water (150 mL) and extractedwith ethyl acetate (100 mL). The ethyl acetate was dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeoil was purified by column chromatography on silica gel (200 g), elutingwith 5% to 50% ethyl acetate/heptane. The procedure generated 2.71 g(20% yield) of 2-[3-(4-bromobutoxy)-propoxy]-tetrahydropyran as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.59 (t, 1H, J=2.4 Hz),3.88-3.78 (m, 2H), 3.53-3.42 (m, 8H), 2.00-1.52 (m, 12H).

Example 26: 3-(4-Bromobutoxy)-propan-1-ol (24)

2-[3-(4-Bromobutoxy)-propoxy]-tetrahydropyran (2.70 g, 9.14 mmol) wasdissolved in methanol (60 mL) under argon at room temperature.p-Toluenesulfonic acid monohydrate (5.21 g, 27.4 mmol) was added and thesolution stirred overnight at room temperature. After 18 h, the solutionwas concentrated under reduced pressure. To the remaining oil was addedethyl acetate (80 mL) and saturated sodium bicarbonate solution (80 mL)in portions. After mixing for 20 minutes, the layers were separated, andthe ethyl acetate extract was dried over sodium sulfate, filtered, andconcentrated. The remaining oil was purified by flash columnchromatography on silica gel (30 g), eluting with 20% to 50% ethylacetate/heptanes. The procedure generated 1.59 g (82% yield) of3-(4-bromobutoxy)-propan-1-ol as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 3.77 (t, 2H, J=5.7 Hz), 3.59 (t, 2H, J=6.0 Hz), 3.50-3.42 (m,4H), 2.00-1.68 (m, 6H).

Example 27: 1-Bromo-4-(3-bromopropoxy)butane (25)

3-(4-Bromobutoxy)-propan-1-ol (1.59 g, 7.53 mmol) was dissolved in THF(25 mL) under argon at room temperature. The flask was placed in a waterbath to maintain room temperature. Carbon tetrabromide (3.75 g, 11.3mmol) and triphenylphosphine (2.94 g, 11.3 mmol) were added, and thereaction stirred for 3 h at room temperature. Heptane (30 mL) was added,and the mixture was filtered and concentrated. The remaining oil waspurified by column chromatography on silica gel (25 g), eluting with 4%ethyl acetate/heptanes. The experiment generated 1.82 g (91% yield)1-bromo-4-(3-bromopropoxy)butane as a clear oil. ¹H NMR (300 MHz, CDCl₃)δ 3.55-3.42 (m, 8H), 2.13-2.05 (m, 2H), 1.99-1.90 (m, 2H), 1.76-1.67 (m,2H).

Example 28: 6-(4-Ethoxycarbonyl-4-methylpentyloxy)-2,2-dimethylhexanoicacid ethyl ester (21)

Ethyl isobutyrate (1.60 g, 13.8 mmol) was dissolved in dry THF (15.0 mL)under argon. The flask was cooled in a dry ice/acetone bath, and 2M LDA(6.5 mL) was added drop-wise over 5-10 minutes. The solution was stirredfor 30 minutes at −78° C. 1-Bromo-4-(3-bromopropoxy)butane (693 mg, 2.53mmol) was added, and the solution slowly warmed to room temperature andstirred overnight. After 18 h, water (25 mL) was added with ethylacetate (25 mL). The layers were separated, and the ethyl acetateextract was washed with 10% hydrochloric acid solution (25 mL), driedover sodium sulfate, filtered, and concentrated. The remaining oil waspurified by column chromatography on silica gel (20 g), eluting with 5%to 10% ethyl acetate/heptanes. The experiment generated 0.74 g (85%yield) of 6-(4-ethoxycarbonyl-4-methylpentyloxy)-2,2-dimethyl-hexanoicacid ethyl ester as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.10 (q,4H, J=7.2 Hz), 3.39-3.35 (m, 4H), 1.58-1.48 (m, 8H), 1.3-1.2 (m, 8H),1.16 (m, 12H). HRMS (ESI): [M+H]⁺=373.2948; found 373.2948

Example 29: 5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (27)

1,5-Pentanediol (40.9 g, 0.45 mol) and p-toluenesulfonic acidmonohydrate (0.66 g, 3.47 mmol) were dissolved in a mixture of THF (100mL) and dichloromethane (30 mL). The flask was cooled in an ice bath,and 3,4-dihydropyran (12.0 g, 0.14 mol) was added drop-wise over 20-30minutes. After 2 hours of stirring, the ice bath was removed, and thereaction stirred at room temperature for 2 hours. After 2 hours, thereaction was slowly poured into water (500 mL) that contained potassiumcarbonate (12 g). The product was extracted with ethyl acetate (2×250mL). The combined ethyl acetate extracts were washed with water (2×250mL) and brine (100 mL), dried over sodium sulfate, filtered, andconcentrated. The crude oil was purified by column chromatography onsilica gel (250 g), eluting with 3:1 heptane/ethyl acetate. Theprocedure generated 20.4 g (72% yield) of5-(tetrahydropyran-2-yloxy)-pentan-1-ol, as a colorless oil. ¹H NMR (300MHz, CDCl₃) δ 4.58 (t, 1H, J=2.7 Hz), 3.90-3.75 (m, 2H), 3.67 (t, 2H,J=0.6 Hz), 3.54-3.36 (m, 2H), 2.37 (m, 2H), 1.85-1.42 (m, 4H), 1.60-1.53(m, 12H).

Example 30: 2-[5-(5-Bromopentyloxy)-pentyloxy]-tetrahydropyran (28)

5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (3.76 g, 19.9 mmol) wasdissolved in dry THF (30 mL) under argon with 60% sodium hydride (0.88g, 22 mmol). The mixture was stirred for 30 minutes at room temperature.1,5-dibromopentane (4.6 g, 20 mmol) was added, and the mixture washeated to reflux for 22 h. After 22 h, the solution was cooled to roomtemperature and poured into water (150 mL) and extracted with ethylacetate (100 mL). The ethyl acetate was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude oil waspurified by column chromatography on silica gel (200 g), eluting with 5%to 50% ethyl acetate/heptane. The procedure generated 1.49 g (21% yield)of 2-[5-(5-bromopentyloxy)-pentyloxy]-tetrahydropyran as a colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ 4.59 (t, 1H, J=2.7 Hz), 3.89-3.70 (m,2H), 3.53-3.35 (m, 8H), 1.91-1.39 (m, 18H).

Example 31: 5-(5-Bromopentyloxy)-pentan-1-ol (29)

2-[5-(5-Bromopentyloxy)-pentyloxy]-tetrahydropyran (1.40 g, 4.15 mmol)was dissolved in methanol (30 mL) under argon at room temperature.p-Toluenesulfonic acid monohydrate (2.38 g, 12.5 mmol) was added, andthe solution stirred overnight at room temperature. After 18 h, thesolution was concentrated under reduced pressure. To the remaining oilwas added ethyl acetate (100 mL) and saturated sodium bicarbonatesolution (80 mL) in portions. After mixing for 20 minutes, the layerswere separated, and the ethyl acetate extract was dried over sodiumsulfate, filtered, and concentrated. The remaining oil was purified byflash column chromatography on silica gel (30 g), eluting with 20% to50% ethyl acetate/heptanes. The procedure generated 1.0 g (95% yield) of5-(5-bromopentyloxy)-pentan-1-ol as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 3.65 (t, 2H, J=6.6 Hz), 3.42 (t, 6H, J=6.6 Hz), 1.93-1.84 (m,2H), 1.62-1.40 (m, 10H).

Example 32: 1-Bromo-5-(5-bromopentyloxy)-pentane (30)

5-(5-Bromopentyloxy)-pentan-1-ol (2.74 g, 10.82 mmol) was dissolved inTHF (50 mL) under argon at room temperature. The flask was placed in awater bath to maintain room temperature. Carbon tetrabromide (5.38 g,16.2 mmol) and triphenylphosphine (4.26 g, 16.2 mmol) were added and thereaction stirred for 3 h at room temperature. Heptane (50 mL) was added,and the mixture was filtered and concentrated. The remaining oil waspurified by column chromatography on silica gel (80 g), eluting with 4%ethyl acetate/heptanes. The experiment generated 1.82 g (91% yield)1-bromo-5-(5-bromopentyloxy)-pentane as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 3.45-3.39 (m, 8H), 1.94-1.85 (m, 4H), 1.65-1.48 (m, 8H).

Example 33: 7-(6-Ethoxycarbonyl-6-methylheptyloxy)-2,2-dimethylheptanoicacid ethyl ester (19)

Ethyl isobutyrate (1.60 g, 13.8 mmol) was dissolved in dry THF (15.0 mL)under argon. The flask was cooled in a dry ice/acetone bath and 2M LDA(6.2 mL) was added drop-wise over 5-10 minutes. The solution was stirredfor 30 minutes at −78° C. 1-Bromo-5-(5-bromopentyloxy)-pentane (800 mg,2.53 mmol) was added and the solution slowly warmed to room temperatureand stirred overnight. After 18 h, water (25 mL) was added with ethylacetate (25 mL). The layers were separated and the ethyl acetate extractwas washed with 10% hydrochloric acid solution (25 mL), dried oversodium sulfate, filtered, and concentrated. The remaining oil waspurified by column chromatography on silica gel (20 g), eluting with 5%to 10% ethyl acetate/heptanes. The experiment generated 0.87 g (89%yield) of 7-(6-ethoxycarbonyl-6-methylheptyloxy)-2,2-dimethylheptanoicacid ethyl ester as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.12 (q,4H, J=7.2 Hz), 3.38 (t, 4H, J=6.6 Hz), 1.58-1.49 (m, 8H), 1.38-1.2 (m,14H), 1.16 (s, 12H). HRMS (ESI): [M+H]⁺=387.3105; found 387.3108

Example 34: 2-[5-(4-Bromobutoxy)-pentyloxy]-tetrahydropyran (31)

5-(Tetrahydropyran-2-yloxy)-pentan-1-ol (6.0 g, 31.8 mmol) was dissolvedin dry THF (100 mL) under argon with 60% sodium hydride (2.60 g, 39.0mmol). The mixture was stirred for 30 minutes at room temperature.1,4-dibromobutane (9.0 g, 41.7 mmol) was added, and the mixture washeated to reflux for 22 h. After 22 h, the solution was cooled to roomtemperature and poured into water (150 mL) and extracted with ethylacetate (100 mL). The ethyl acetate was dried over sodium sulfate,filtered, and concentrated under reduced pressure. The crude oil waspurified by column chromatography on silica gel (200 g), eluting with 5%to 50% ethyl acetate/heptane. The procedure generated 2.41 g (24% yield)of 2-[5-(4-bromobutoxy)-pentyloxy]-tetrahydropyran as a colorless oil.¹H NMR (300 MHz, CDCl₃) δ 4.57 (t, 1H, J=2.7 Hz), 3.89-3.70 (m, 2H),3.51-3.47 (m, 8H), 1.99-1.38 (m, 16H).

Example 35: 5-(4-Bromobutoxy)-pentan-1-ol (35)

2-[5-(4-Bromobutoxy)-pentyloxy]-tetrahydropyran (2.41 g, 7.45 mmol) wasdissolved in methanol (60 mL) under argon at room temperature.p-Toluenesulfonic acid monohydrate (4.25 g, 22.6 mmol) was added, andthe solution stirred overnight at room temperature. After 18 h, thesolution was concentrated under reduced pressure. To the remaining oilwas added ethyl acetate (80 mL) and saturated sodium bicarbonatesolution (80 mL) in portions. After mixing for 20 minutes, the layerswere separated, and the ethyl acetate extract was dried over sodiumsulfate, filtered, and concentrated. The remaining oil was purified byflash column chromatography on silica gel (25 g), eluting with 20% to50% ethyl acetate/heptanes. The procedure generated 1.62 g (91% yield)of 5-(4-bromobutoxy)-pentan-1-ol as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ 3.65 (m, 2H), 3.42 (t, 6H, J=6.6 Hz), 3.47-3.39 (m, 6H),1.99-1.90 (m, 2H), 1.76-1.32 (m, 6H).

Example 36: 1-Bromo-5-(4-bromobutoxy)-pentane (32)

5-(4-Bromobutoxy)-pentan-1-ol (1.62 g, 6.77 mmol) was dissolved in THF(30 mL) under argon at room temperature. The flask was placed in a waterbath to maintain room temperature. Carbon tetrabromide (3.36 g, 10.2mmol) and triphenylphosphine (2.66 g, 10.2 mmol) were added, and thereaction stirred for 3 h at room temperature. Heptane (50 mL) was addedand the mixture was filtered and concentrated. The remaining oil waspurified by column chromatography on silica gel (40 g), eluting with 4%ethyl acetate/heptanes. The experiment generated 1.40 g (70% yield)1-bromo-5-(4-bromobutoxy)-pentane as a clear oil. ¹H NMR (300 MHz,CDCl₃) δ 3.47-3.39 (m, 8H), 2.0-1.84 (m, 4H), 1.76-1.47 (m, 6H).

Example 37: 7-(5-Ethoxycarbonyl-5-methylhexyloxy)-2,2-dimethylheptanoicacid ethyl ester (33)

Ethyl isobutyrate (1.60 g, 13.8 mmol) was dissolved in dry THF (15.0 mL)under argon. The flask was cooled in a dry ice/acetone bath and 2M LDA(6.5 mL) was added drop-wise over 5-10 minutes. The solution was stirredfor 30 minutes at −78° C. 1-Bromo-5-(4-bromobutoxy)-pentane (765 mg,2.53 mmol) was added, and the solution slowly warmed to room temperatureand stirred overnight. After 18 h, water (25 mL) was added with ethylacetate (25 mL). The layers were separated, and the ethyl acetateextract was washed with 10% hydrochloric acid solution (25 mL), driedover sodium sulfate, filtered, and concentrated. The remaining oil waspurified by column chromatography on silica gel (20 g), eluting with 5%to 10% ethyl acetate/heptanes. The experiment generated 0.74 g (79%yield) of 7-(5-Ethoxycarbonyl-5-methylhexyloxy)-2,2-dimethylheptanoicacid ethyl ester as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ 4.14 (q,4H, J=7.2 Hz), 3.43-3.38 (m, 4H), 1.59-1.55 (m, 8H), 1.40-1.2 (m, 12H),1.19 (m, 12H). HRMS (ESI): [M+H]⁺=373.2948; found 373.2948

Example 38: 3,3-Dimethyl-oxepan-2-one (25)

Caprolactone (2.0 g, 17.5 mmol) was dissolved in dry THF (40 mL) underargon. The flask was cooled in a dry ice/acetone bath, and 2M LDA (10mL, 20 mmol) was added drop-wise over 5-10 minutes. The solution wasstirred for 50 minutes at −78° C. Iodomethane (2.9 g, 20.5 mmol) wasadded, and the solution slowly warmed by removing the acetone bath andreplacing it with an ice/water bath. After 1 hour, the ice/water bathwas replaced with a dry ice/acetone bath, and 2M LDA (10 mL, 20 mmol)was added drop-wise over 5-10 minutes. The solution was stirred for 50minutes at −78° C. Iodomethane (5.8 g, 41 mmol) was added, and thesolution slowly warmed to 0° C. over 2 h. Water (50 mL) was added withdiethyl ether (25 mL). The layers were separated, and the ether extractwas washed with 10% hydrochloric acid solution (25 mL), dried oversodium sulfate, filtered, and concentrated. The remaining oil waspurified by column chromatography on silica gel (50 g), eluting with 40%ethyl acetate/heptanes. The experiment generated 0.40 g (16% yield) of3,3-dimethyl-oxepan-2-one as a colorless oil. ¹H NMR (300 MHz, CDCl₃) δ4.04 (t, 2H, J=6.0 Hz), 1.65-1.50 (m, 4H), 1.30-1.20 (m, 2H), 1.16 (s,6H).

OTHER EMBODIMENTS

The foregoing disclosure has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications can be made while remainingwithin the spirit and scope of the invention. It will be obvious to oneof skill in the art that changes and modifications can be practicedwithin the scope of the appended claims. Therefore, it is to beunderstood that the above description is intended to be illustrative andnot restrictive.

The scope of the invention should, therefore, be determined not withreference to the above description, but should instead be determinedwith reference to the following appended claims, along with the fullscope of equivalents to which such claims are entitled.

1.-24. (canceled)
 25. A process for making a compound of formula (48):

wherein: R²¹ is alkyl; each R²² and R²³ is independently alkyl; and eachm is independently 0, 1, 2, 3, or 4; comprising: (a) allowing a compoundof formula (46):

to react with a Br, Cl, or I source to provide a compound of formula(47):

wherein X²⁴ is Br, Cl, or I; and (b) allowing a compound of formula (46)to react with the compound of formula (47) in the presence of base toprovide the compound of formula (48).
 26. The process of claim 25,further comprising allowing a compound of formula (45):

to react with potassium tert-butoxide to provide a compound of formula(46) wherein R²¹ is tert-butyl.
 27. The process of claim 26, furthercomprising allowing a compound of formula (43a):

wherein M²³ is Li or Zn; to react with an alkyl halide of formula (44):R²³—X²³   44 wherein X²³ is Br, Cl, or I; to provide the compound offormula (45).
 28. The process of claim 27, further comprising allowing acompound of formula (43):

to react with a lithium or zinc deprotonating reagent to provide thecompound of formula (43a).
 29. The process of claim 28, furthercomprising allowing a compound of formula (41a):

wherein M²² is Li or Zn; to react with an alkyl halide of formula (42):R²²—X²²   42 wherein X²² is Br, Cl, or I; to provide the compound offormula (43).
 30. The process of claim 29, further comprising allowing acompound of formula (41):

to react with a lithium or zinc deprotonating reagent to provide thecompound of formula (41a).
 31. A process for making a compound offormula (49)

comprising: (a) performing the process of claim 25; (b) hydrolyzing thecompound of formula (48) in the presence of an alkali metal salt, alkalimetal base, alkali metal oxide, alkaline earth metal salt, alkalineearth metal base or alkaline earth metal oxide; and (c) acidifying theproduct of step (b) to provide the compound of formula (49).
 32. Aprocess for making a compound of formula (49)

comprising: (a) performing the process of claim 25 where R²¹ istert-butyl and (b) allowing the compound of formula (48) to react withtrifluoroacetic acid to provide the compound of formula (49).
 33. Theprocess of claim 31 or 32, wherein the compound of formula (49) is


34. A process for making a compound of formula (50):

wherein M¹ is Ca²⁺ and x is 1; comprising: (a) performing the process ofclaim 31; and (b) allowing the compound of formula (49) to react withCaO or Ca(OH)₂ to provide the compound of formula (50).
 35. A processfor making a compound of formula (50):

wherein M¹ is Ca²⁺ and x is 1; comprising: (a) performing the process ofclaim 32; and (b) allowing the compound of formula (49) to react withCaO or Ca(OH)₂ to provide the compound of formula (50).
 36. The processof claim 34, wherein each R²² is methyl, each R²³ is methyl and each mis
 1. 37. The process of claim 35, wherein each R²² is methyl, each R²³is methyl and each m is
 1. 38. The process of claim 36, wherein thecompound of formula (49) reacts with CaO or Ca(OH)₂ in absolute ethanolat reflux and provides compound (4)

as an ethanolic mixture.
 39. The process of claim 37, wherein thecompound of formula (49) reacts with CaO Ca(OH)₂ in absolute ethanol atreflux and provides compound (4)

as an ethanolic mixture.
 40. The process of claim 38, furthercomprising: allowing the ethanolic mixture to cool to room temperature;diluting the ethanolic mixture with methyl t-butyl ether; allowingcompound (4) to precipitate from the ethanolic mixture; and filteringcompound (4) from the ethanolic mixture to provide a filtered compound(4).
 41. The process of claim 39, further comprising: allowing theethanolic mixture to cool to room temperature; diluting the ethanolicmixture with methyl t-butyl ether; allowing compound (4) to precipitatefrom the ethanolic mixture; and filtering compound (4) from theethanolic mixture to provide a filtered compound (4).
 42. A process formaking a hydrate of compound (4), comprising: performing the process ofclaim 40; drying the filtered compound (4); and hydrating the filteredcompound (4) to provide the hydrate of compound (4).
 43. A process formaking a hydrate of compound (4), comprising: performing the process ofclaim 41; drying the filtered compound (4); and hydrating the filteredcompound (4) to provide the hydrate of compound (4).
 44. The process ofclaim 42, wherein the hydrating is performed at 100° C.
 45. The processof claim 43, wherein the hydrating is performed at 100° C.
 46. A processfor making a compound of formula (50):

wherein M¹ is an alkaline earth metal and x is 1 or M¹ is an alkalimetal and x is 2; comprising: (a) performing the process of claim 25;and (b) hydrolyzing the compound of formula (48) in the presence of (i)an alkaline earth metal salt, alkaline earth metal base or alkalineearth metal oxide to provide the compound of formula (50), wherein M¹ isan alkaline earth metal and x is 1, or (ii) an alkali metal salt, alkalimetal base or alkali metal oxide to provide the compound of formula(50), wherein M¹ is an alkali metal and x is
 2. 47. The process of claim46, wherein M¹ is Ca²⁺ and x is 1, or M¹ is K⁺ and x is 2; andcomprising hydrolyzing the compound of formula (48) in the presence of(a) potassium hydroxide to provide the compound of formula (50) whereinM¹ is K⁺ and x is 2, or (b) calcium hydroxide or calcium oxide toprovide the compound of formula (50) wherein M¹ is Ca²⁺ and x is
 1. 48.A process for making a compound of formula (49):

wherein: each R²² and R²³ is independently alkyl; and each m isindependently 0, 1, 2, 3, or 4; comprising: (a) allowing a compound offormula (41):

to react with a lithium or zinc deprotonating reagent to provide acompound of formula (41a):

wherein M²² is Li or Zn; (b) reacting the compound of formula (41a) withan alkyl halide of formula (42):R²²—X²²   42 wherein X²² is Br, Cl, or I; to provide a compound offormula (43):

(c) allowing the compound of formula (43) to react with a lithium orzinc deprotonating reagent to provide a compound of formula (43a):

wherein M²³ is Li or Zn; (d) allowing the compound of formula (43a) toreact with an alkyl halide of formula (44):R²³—X²³   44 wherein X²³ is Br, Cl, or I; to provide a compound offormula (45):

(e) allowing the compound of formula (45) to react with potassiumtert-butoxide to provide a compound of formula (46):

where R²¹ is tert-butyl; (f) allowing the compound of formula (46) toreact with a Br, Cl, or I source to provide a compound of formula (47):

wherein X²⁴ is Br, Cl, or I; (g) allowing the compound of formula (46)to react with the compound of formula (47) in the presence of base toprovide a compound of formula (48):

(h) allowing the compound of formula (48) to react with trifluoroaceticacid to provide the compound of formula (49)


49. The process of claim 48, wherein the compound of formula (49) is:


50. A process for making a compound of formula (50):

wherein M¹ is an alkaline earth metal and x is 1 or M¹ is an alkalimetal and x is 2; comprising: (a) performing the process of claim 31;(b) allowing the compound of formula (49) to react with an aqueoussolution of hydroxide or oxide of an alkali metal or earth alkalinemetal in water-miscible solvent; and (c) precipitating the compound offormula (50).
 51. A process for making a compound of formula (50):

wherein M¹ is an alkaline earth metal and x is 1 or M¹ is an alkalimetal and x is 2; comprising: (a) performing the process of claim 32;(b) allowing the compound of formula (49) to react with an aqueoussolution of hydroxide or oxide of an alkali metal or earth alkalinemetal in water-miscible solvent; and (c) precipitating the compound offormula (50).
 52. A process for making a compound of formula (45):

wherein: R²² and R²³ are each independently alkyl; and m is 0, 1, 2, 3,or 4; comprising: (a) allowing a compound of formula (41):

to react with a lithium or zinc deprotonating reagent to produce acompound of formula (41a):

wherein M²² is Li or Zn; (b) reacting the compound of formula (41a) withan alkyl halide of formula (42):R²²—X²²   42 wherein X²² is Br, Cl, or I; to provide a compound offormula (43):

(c) allowing the compound of formula (43) to react with a lithium orzinc deprotonating reagent to provide a compound of formula (43a):

wherein M²³ is Li or Zn; and (d) allowing the compound of formula (43a)with an alkyl halide of formula (44):R²³—X²³   44 wherein X²³ is Br, Cl, or I; to provide the compound offormula (45).
 53. A process for making a compound of formula (IV):

wherein: M¹ is an alkaline earth metal and x is 1 or M¹ is an alkalimetal and x is 2; each R² and R³ is independently alkyl; and n and m areindependently 0, 1, 2, 3, or 4; comprising: allowing a compound offormula (III)

wherein each R¹ is independently alkyl, to react with an aqueoussolution of an alkali metal hydroxide, alkali metal oxide, alkalineearth metal hydroxide or alkaline earth metal oxide in a water-misciblesolvent to provide the compound of formula (IV).
 54. The process ofclaim 53, further comprising precipitating the compound of formula (IV)from an organic solvent.
 55. The process of claim 53, wherein thewater-miscible solvent is DMF, DMSO, acetone, methanol, isopropylalcohol, or ethanol.
 56. The process of claim 53, wherein the watermiscible solvent is DMSO.
 57. The process of claim 53, wherein: each R²and R³ is methyl; m and n are 1; M¹ is Ca²⁺; and x is
 1. 58. A processfor making compound (4)

comprising allowing a compound of formula (III)

wherein each R¹ is independently alkyl and each R² and R³ is methyl, toreact with an aqueous solution of CaO or Ca(OH)₂ in water-misciblesolvent to provide compound (4).
 59. The process of claim 25, furthercomprising debenzylating tert-butyl 6-benzyloxy-2,2-dimethylhexanoate toprovide the compound of formula (46)

wherein R²¹ is tert-butyl, each R²² and R²³ is independently methyl, andm is
 1. 60. The process of claim 59, wherein the debenzylating isperformed in the presence of palladium on carbon.
 61. The process ofclaim 59, further comprising allowing tert-butyl isobutyrate to reactwith benzyl 4-bromobutyl ether in the presence of base to provide thetert-butyl 6-benzyloxy-2,2-dimethylhexanoate.
 62. The process of claim59, further comprising allowing 6-benzyloxy-2,2-dimethylhexanoic acid toreact with tert-butyl-dicyclohexyl isourea to provide the tert-butyl6-benzyloxy-2,2-dimethylhexanoate.
 63. The process of claim 62, furthercomprising allowing ethyl 6-benzyloxy-2,2-dimethylhexanoate to hydrolyzein the presence of base to provide 6-benzyloxy-2,2-dimethylhexanoicacid.